Ophthalmic composition for treatment of dry eye disease

ABSTRACT

The invention provides ophthalmic compositions comprising about 0.1% (w/v) cyclosporine dissolved in 1-(perfluorobutyl)pentane for use in the topical treatment of dry eye disease. The invention further provides kits comprising such compositions for the same use.

BACKGROUND OF THE INVENTION

Keratoconjunctivitis sicca, also known as dry eye disease ordysfunctional tear syndrome, is today understood as a multifunctionaldisorder of the tear film and of the ocular surface which results indiscomfort, visual disturbance, and often even in ocular surface damagecaused by tear film instability. Estimates of the prevalence of dry eyevary considerably, depending on the criteria used to define the disease,but in the U.S., it has been estimated that as many as 3.2 million womenand 1.7 million men over the age of 50 have dry eye, with a projected40% increase in number of patients affected by 2030.

A pharmacological treatment option for dry eye disease is cyclosporine.Cyclosporine is available, at least in the US as an approved medicine inthe form of an ophthalmic (o/w) emulsion (Restasis®). This product isindicated to increase tear production in patients whose tear productionis presumed to be suppressed due to ocular inflammation associated withkeratoconjunctivis sicca.

WO2011/073134 A1 discloses pharmaceutical compositions in the form ofsolutions comprising cyclosporine and a semifluorinated alkane as aliquid vehicle which may be administered to the eye of a patient, suchas for the treatment of keratoconjunctivitis sicca, for instancecompositions comprising cyclosporine in semifluorinated alkane1-(perfluorobutyl)pentane (F4H5) in the presence of ethanol as aco-solvent.

Gehlsen et al. (Investigative Ophthalmology & Visual Science June 2015,Vol. 56, 319) describes a study to test the use of CsA in (F4H5) fortopical therapy in a mouse model of experimental dry eye disease.Gehlsen et al describes that in the study, topical therapy was performedon mice with induced experimental dry eye disease 3×/day (5 μL/eye).Gehlsen et al. however does not disclose a treatment or dosing regimenfor the treatment of dry eye disease in human subjects.

WO2018/115097 describes a dosing regimen for the treatment of patientswith dry eye disease, based on ophthalmic compositions comprising about0.05 to 0.1% (w/v) cyclosporine dissolved in 1-(perfluorobutyl)pentane.This document however does not disclose a targeted treatment in respectof specific symptoms associated with dry eye disease and the frequencyof their occurrence. The method of treatment also does not disclose acomposition for use in a treatment of patients meeting a specific set ofdry eye disease signs and symptoms.

Accordingly there is still a need for means and method for treatingpatients meeting certain criteria for dry eye disease, as well as fortreating patients for which certain symptoms of dry eye disease isparticularly prevalent. It is thus an object of the present invention toprovide composition for use which is effective in addressing thesespecific aspects. Further objects of the invention will be clear on thebasis of the following description of the invention, examples andclaims.

SUMMARY OF THE INVENTION

In a first aspect, the invention relates to an ophthalmic compositioncomprising 0.1% (w/v) cyclosporine dissolved in1-(perfluorobutyl)pentane for use in a method of treatingkeratoconjunctivitis sicca (dry eye disease), wherein the methodcomprises a step of topically administering the composition to an eye ofa patient, and wherein the patient has a total ocular surface diseaseindex (OSDI) score of equal or greater than 45. In other embodiments,the patient has a total ocular surface disease index (OSDI) score ofequal or greater than 55.

In a second aspect, the invention relates to an ophthalmic compositioncomprising 0.1% (w/v) cyclosporine dissolved in1-(perfluorobutyl)pentane for use in: a) a method of treating and/orameliorating the symptoms associated with keratoconjunctivitis sicca(dry eyes), wherein the symptoms are dryness and blurred vision; and/orb) for use in a method of treating and/or ameliorating the awareness ofsymptoms of dry eyes and the frequency of dryness.

DESCRIPTION OF THE DRAWINGS

FIG. 1. Total ocular surface disease index (OSDI)—depicted is the changefrom baseline of the total OSDI score (mean) at 2 weeks, 4 weeks, 8weeks and 12 weeks of treatment (2 times per day) with vehicle (F4H5;N=90) and CyclASol 0.1% Ophthalmic Solution (clear ophthalmic solutionof Cyclosporine A dissolved in 1-(perfluorobutyl)pentane, with 1.0% w/wethanol; N=79), in subjects with a baseline total OSDI of 45 or greater.

FIG. 2. Total ocular surface disease index (OSDI)—depicted is the changefrom baseline of the total OSDI score (mean) at 2 weeks, 4 weeks, 8weeks and 12 weeks of treatment (two times per day) with vehicle (F4H5;N=55) and CyclASol 0.1% Ophthalmic Solution (clear ophthalmic solutionof Cyclosporine A dissolved in 1-(perfluorobutyl)pentane, with 1.0% w/wethanol; N=41), in subjects with a baseline total OSDI of 55 or greater.

FIG. 3. VAS symptom improvements. Depicted is the mean change frombaseline (Visit 1) after 4 weeks of the VAS score in study subjectsadministered (2 times per day) with vehicle (F4H5; N=165) and CyclASol0.1% Ophthalmic Solution (N=160; clear ophthalmic solution ofCyclosporine A dissolved in 1-(perfluorobutyl)pentane, with 1.0% w/wethanol) for: blurred vision, awareness of symptoms of dry eye,frequency of dryness, severity of dryness, and combined frequency andseverity of dryness.

FIG. 4. Total ocular surface disease index (OSDI)—depicted is the changefrom baseline of the total OSDI score (mean) at 2 weeks, 4 weeks, 8weeks and 12 weeks of treatment (2 times per day) with vehicle (F4H5;N=166) and CyclASol 0.1% Ophthalmic Solution (clear ophthalmic solutionof Cyclosporine A dissolved in 1-(perfluorobutyl)pentane, with 1.0% w/wethanol; N=162), for the entire population of subjects.

FIG. 5. Total corneal fluorescein staining (NEI scale)-depicted is thechange from baseline of the total corneal fluorescein staining (mean) at2 weeks, 4 weeks, 8 weeks and 12 weeks of treatment (2 times per day)with vehicle (F4H5; N=165) and CyclASol 0.1% Ophthalmic Solution (clearophthalmic solution of Cyclosporine A dissolved in1-(perfluorobutyl)pentane, with 1.0% w/w ethanol; N=160), for the entirepopulation of subjects. Error bars show standard error of the mean(SEM).

FIG. 6. Total corneal fluorescein staining responder analysis (≥3 gradesimprovement) after 4 weeks of treatment. Compared are the proportions ofsubjects, respectively treated with CyclAsol 0.1% and vehicle, with agrades improvement in the total corneal fluorescein staining (tCFS).

FIG. 7. Central corneal fluorescein staining (NEI scale) responderanalysis (≥1 grade improvement) after 4 weeks of treatment. Compared arethe proportions of subjects, respectively treated with CyclAsol 0.1% andvehicle, with a 1 grade improvement in the central corneal fluoresceinstaining (cCFS).

FIG. 8. Conjunctival lissamine green staining responder analysis (≥2grades improvement) after 12 weeks of treatment. Compared are theproportions of subjects, respectively treated with CyclAsol 0.1% andvehicle, with a ≥2 grades improvement in the conjunctival lissaminegreen staining.

FIG. 9. Conjunctival lissamine green staining (change from baseline onOxford scale)-depicted is the change from baseline of the conjunctivallissamine green staining value (mean) at 4 weeks and 12 weeks oftreatment (2 times per day) with vehicle (F4H5) and CyclASol 0.1%Ophthalmic Solution (clear ophthalmic solution of Cyclosporine Adissolved in 1-(perfluorobutyl)pentane, with 1.0% w/w ethanol), for theentire population of subjects. Error bars show the standard error of themean (SEM).

FIG. 10. International Reading Speed Texts (IResT) critical printsize—depicted is the number of words read per minute for a) all thepatients at baseline (N=322); b) the tCFS non responder group (N=172)after four weeks; and c) the tCFS responder group (N=150) after fourweeks, wherein tCFS responders are subjects whose tCFS score decreasedof 3 or more units (NEI) after four weeks.

FIG. 11. International Reading Speed Texts (IResT) critical printsize—depicted is the number of words read per minute for the CyclASolgroup of patients at baseline (N=157), the CyclASol tCFS non respondersafter four weeks (N=74) and the CyclASol tCFS responders after fourweeks (N=83), respectively.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to, in a first aspect, an ophthalmiccomposition comprising 0.1% (w/v) cyclosporine dissolved in1-(perfluorobutyl)pentane for use in a method of treating ofkeratoconjunctivitis sicca (dry eye disease), wherein the methodcomprises a step of topically administering the composition to an eye ofa patient, and wherein the patient has a total ocular surface diseaseindex (OSDI) score of equal or greater than 45.

Dry eye disease (also abbreviated as DED, and which also may be known askeratoconjunctivitis sicca, dysfunctional tear syndrome or dry eyesyndrome) is a complex disease that results in symptoms of discomfort,visual disturbance, and tear film instability, and which createspotential for damage of the ocular surface. It may be accompanied byincreased osmolarity of the tear film and inflammation of the ocularsurface. A patient having keratoconjunctivitis sicca may experience anyone of, or a combination of tear hyperosmolarity, tear film instabilityor abnormalities in the lipid layer composition of the tear film.

Two major categories of keratoconjunctivitis sicca or dry eye disease(DED) are distinguished today, which are aqueous-deficient DED andevaporative DED. Within the class of aqueous-deficient forms of DED, twomajor subtypes may be differentiated, Sjögren and non-Sjögren.

Sjögren syndrome patients suffer from autoimmune disorders in which thelacrimal glands are invaded by activated T-cells, which leads not onlyto dry eye disease but also to a dry mouth condition. The Sjögrensyndrome can be a primary disease or can result from other autoimmunediseases, such as systemic lupus erythrematosus or rheumathroidarthritis. Non-Sjögren patients suffering from an aqueous-deficient DEDusually have a lacrimal gland insufficiency, lacrimal duct obstructionor reflex hyposecretion.

The second major class, evaporative dry eye disease, is also somewhatheterogeneous and can develop as a result of diverse root causes. One ofthe major causes is meibomian gland disease or dysfunction, eyelidaperture disorders, blink disorders (as in Parkinson's disease) orocular surface disorders (as in allergic conjunctivitis).

Symptoms of dry eye disease may include, but are not limited to, anyone, or combination of, the following: a dry, scratchy, gritty, or sandyfeeling in the eye; foreign body sensation; pain or soreness; stingingor burning; itching; increased blinking; eye fatigue; photophobia;blurry vision; redness; mucus discharge; contact lens intolerance; andexcessive reflex tearing. It is understood that not all patientssuffering from dry eye disease may exhibit all of these symptomssimultaneously.

Subjects suffering from dry eye disease may experience symptoms whichindividually, or collectively, such as blurring, pain, irritation whichmay contribute to visual impairment or difficulties which can bereflected by a negative effect on the subject's performance infunctional tasks where visual performance and acuity may be essential.Dry eye disease may also lead, or contribute to corneal surface damagefor example to the central cornea.

As understood herein, the term “dry eye disease” individually may referto any one or combination of the subtypes or categories, or root causesas described herein and that any symptom or aspect or pathophysiologicalconsequences of dry eye disease may be addressed.

The severity of dry eye disease in subjects or patients can beclassified and scored using one or more, or a combination of standardtests based on assessment of dry eye disease symptoms. For example, theseverity of dry eye disease may be determined using tests based on theassessment of patient perception of ocular symptoms and their effect onvision, based on questionnaires such as the Ocular Surface Disease Index(OSDI) questionnaire, which is a 12-item questionnaire focussed onsymptoms of ocular irritation associated with dry eye disease and theirimpact on daily activities and lifestyle of the patient during the weekpreceding their assessment.

The OSDI test is scored using a scale of 0 to 4 for each question. Forexample, as part of the test patients may be asked questions regardingproblems with blurred vision during the last week, and are asked toindicate, if applicable, either 0 for none of the time, 1 for some ofthe time, 2 for half of the time, 3 for most of the time or 4 for all ofthe time. The scores from the questionnaire are totalled and assessed ona scale of 0 to 100, with higher scores representing greaterdegree/severity and impact of dry eye disease. In the context of thepresent invention, it has been found that the compositions as definedare particularly effective especially in the treatment of dry eyedisease in patients having at baseline, prior to commencement oftreatment with the composition, a total OSDI score of equal, or greaterthan 45; or patients with a total OSDI score of equal, or greater than55.

The dry eye symptom visual analogue scale (VAS) is a test in the form ofa questionnaire, where subjects are asked to rate their ocular symptoms(both eyes simultaneously) by placing a vertical mark on the horizontalline to indicate the level of discomfort from a scale of 0 to 100% withregards to dryness, sticky feeling, burning/stinging, foreign bodysensation, itching, blurred vision, sensitivity to light, and pain,wherein 0 corresponds to “no discomfort” while 100% corresponds to“maximal discomfort”. The VAS test also assesses the frequency inoccurrence of dryness experienced by the subject, as well as thepercentage of time the subject is aware of experiencing the symptoms ofdry eye, (with 0 corresponding to ‘never’ and 100% corresponding to ‘allof the time’). The VAS test may be conducted at various time points toassess the effectiveness and patient response in respect to impact oftherapy on these symptoms of dry eye disease.

Signs of dry eye disease in a patient's eye may also be evaluated anddetermined using any combination of objective clinical measures such asthe Schirmer test type 1, fluorescein staining and/or lissamine greenstaining of the cornea and conjunctiva, and tear-film break up time(TFBUT, or TBUT) as a measurement of tear quality. Therapeutic efficacymay also be assessed by comparison of measurements for each orcombination of these clinical measures, obtained at various time pointsduring a given treatment period, also in combination or conjunction withany of the symptom assessments described above.

In one embodiment of the invention described herein, the subject orpatient has, prior to treatment with the compositions defined herein, atotal OSDI scoring of equal or greater than 45, or preferably equal orgreater than 55, as well as, in at least one eye, or alternatively botheyes, any one or combination of the following:

i. a total corneal fluorescein staining score of ≥10 according to NEIgrading (i.e. sum of scoring for the inferior, superior, central, nasal,and temporal cornea regions equal to or greater than 10);ii. a total lissamine green conjunctival score (sum of temporal andnasal regions) of ≥2 according to the Oxford scale;iii. a Schirmer's Test I score of between 1 mm and 10 mm or anycombination thereof.

Cyclosporine is a pharmacological treatment option for dry eye disease,which is available as a prescription medication, for example, in the USin the form of an 0.05% ophthalmic (o/w) emulsion (Restasis®). Thisproduct is indicated to increase tear production in patients whose tearproduction is presumed to be suppressed due to ocular inflammationassociated with keratoconjunctivis sicca. Restasis® is administeredtwice a day in each eye approximately 12 hours apart. It is packaged insingle-vials. (Prescribing Information, Restasis®).

Cyclosporine (synonyms include cyclosporin A, CsA, or ciclosporin) is acyclic nonribosomal peptide comprising 11 amino acids with the empiricalformula C₆₂H₁₁₁N₁₁O₁₂ and molecular weight of 1202.61. It is animmunosuppressant drug that is widely used in post-allergenic organtransplant, to reduce the activity of the patient's immune system andthereby, the risk of organ rejection. Cyclosporine is typically providedas a colourless or white powder. Cyclosporine is thought to bind to thecytosolic protein cyclophilin (immunophilin) of immunocompetentlymphocytes, especially T-lymphocytes. This complex of cyclosporin andcyclophilin inhibits calcineurin, which, under normal circumstances, isresponsible for activating the transcription of interleukin 2. It alsoinhibits lymphokine production and interleukin release and, therefore,leads to a reduced function of effector T-cells.

The ophthalmic composition according to the present invention employs,as a liquid vehicle for the cyclosporine, the compound1-(perfluorobutyl)pentane. 1-(perfluorobutyl)pentane is asemifluorinated alkane with the chemical formula F(CF₂)₄(CH₂)₅H. It isan inert, water-insoluble liquid, with a density of 1.284 g/cm³ at 25°C. and refractive index of 1.3204 at 20° C. Alternative nomenclature forthis compound includes F4H5, wherein F denotes a linear perfluorinatedalkane segment comprising 4 carbon atoms and wherein H denotes a linearand non-fluorinated alkane hydrocarbon segment of 5 carbon atoms.Preferably, the 1-(perfluorobutyl)pentane is substantially free ofwater.

In one embodiment, the ophthalmic composition for any one of the usesaccording to the present invention may comprise or consist, further tothe cyclosporine featured in any one the preferred concentrations of theinvention, of at least about 97% (w/w) or more preferably, of at leastabout 98% (w/w), or of at least about 99% (w/w) of1-(perfluorobutyl)pentane, based on the total weight of the ophthalmiccomposition (final dosage form). In another embodiment, thepharmaceutical composition for any one of the uses according to thepresent invention may consist of, in addition to the cyclosporine in anamount or concentration as defined herein, from about 95.0 to about99.99% (w/w), or about 96.0 to about 99.99% (w/w), or from about 98.0 to99.99% (w/w), or from about 99.999 to about 99.9999% (w/w) of1-(perfluorobutyl)pentane, based on the total weight of the finalcomposition.

In another embodiment, the ophthalmic composition for any one of theuses described herein for the present invention may optionally furthercomprise 2-(perfluorobutyl)pentane. The composition, in addition to1-(perfluorobutyl)pentane, may optionally comprise minor amounts of2-(perfluorobutyl)pentane, of up to 2% (w/w), or up to 1% (w/w), or upto 0.5% (w/w).

The concentration of cyclosporine in the ophthalmic compositions for anyone of the uses according to the invention is 0.1% (w/v) of thecomposition.

Unless otherwise indicated, the term “% (w/v)” denotes the amount of acomponent of a composition as a weight percentage in relation to thetotal volume of the composition (with ‘w’ denoting the weight and ‘v’denoting volume). For example 0.1% (w/v) would correspond to 1.0 mg of acomponent in 1 mL of the composition. Unless otherwise indicated, theterm “% (w/w)” or wt % refers to the amount of a component of acomposition as a weight percentage in relation to the total weight ofthe composition (with ‘w’ denoting weight).

The term ‘about’ as used herein and in reference or connection to aparameter, for example such as the concentration of cyclosporinedissolved in the composition or the volume featured in a single dose orapplied liquid drop of the composition includes the precise value asdefined, as well as any value falling within the degree of variabilityusually observed in measuring or determining these parameters using thestandard techniques and equipment known in the art and field.

The ophthalmic composition as defined herein may be used for thetreatment of human subjects with dry eye disease, as well as for anyrelated conditions, or signs and symptoms associated therewith.

In a first aspect, the present invention provides for the followingitems:

-   1.1 An ophthalmic composition comprising 0.1% (w/v) cyclosporine    dissolved in 1-(perfluorobutyl)pentane for use in a method of    treating keratoconjunctivitis sicca (dry eye disease), wherein the    method comprises a step of topically administering the composition    to an eye of a patient, wherein the patient has a total ocular    surface disease index (OSDI) score of equal or greater than 45.-   1.2 Composition for use of 1.1, wherein the patient has a total    ocular surface disease index (OSDI) score of equal or greater than    55.-   1.3 The ophthalmic composition for use of any one of the preceding    items, wherein the composition comprises up to about 1.0% (w/w)    ethanol.-   1.4 The ophthalmic composition for use of any one of the preceding    items, wherein the composition consists of 0.1% (w/v) cyclosporine,    1-(perfluorobutyl)pentane (F4H5) and up to 1.0% (w/w) ethanol.-   1.5 The composition for use of any of the preceding items, wherein    the ophthalmic composition is administered to the surface of the    cornea and/or conjunctiva in the form of a liquid drop.-   1.6 The composition for use in any of the preceding items, wherein    the composition is administered as a single drop having a volume of    about 8 to 11 μL, preferably of about 8 to 10 μL.-   1.7 The composition for use of any of the preceding items, wherein    the composition is administered in a dose of a single drop per eye    one time per day in volume of about 8-10 μL.-   1.8 The ophthalmic composition for use according to any one of the    preceding items, wherein the composition is administered as a single    drop having a volume of about 10 μl.-   1.9 The ophthalmic composition for use of any one of the preceding    items, wherein the composition is administered twice a day per eye.-   1.10 The composition for use in any of the preceding items, wherein    the composition is administered in a dose of a single drop per eye    twice per day in net volume of about 16-20 μL.-   1.11 The composition for use according to any one of the preceding    items, wherein the dry eye disease is aqueous-deficient dry eye    disease.-   1.12 The composition for use according to any of the preceding    items, wherein the dry eye disease is evaporative dry eye disease.-   1.13 The composition for use according to any of the preceding    items, wherein the patient is non-responsive, or insufficiently    responsive, to treatment with aqueous ophthalmic eye drop    compositions (e.g. aqueous cyclosporin emulsion eye drops).-   1.14 The composition for use of any of the preceding items, wherein    the time interval between topical administration of the composition    to the eye or eye surface of a first dose and a second dose is at    least 4 hours, or at least 6 hours, or at least 12 hours.-   1.15 The composition for use of any of the preceding items, wherein    the duration of the treatment is for at least 2 weeks, or at least 4    weeks, or at least 6 weeks, or at least 8 weeks, or at least 12    weeks.-   1.16 The composition for use of any of the preceding items wherein    the patient is a human patient.-   1.17 The composition for use of any of the preceding items, wherein    the patient is a female patient.-   1.18 The composition for use of any of the preceding items, wherein    the patient is a male patient.-   1.19 The composition for use of any of the preceding items, wherein    the patient is aged 20-80 years old at the time of treatment, e.g.,    20-50 years old, or 20-70 years old, or 30-80 years old, or 30-50    years old, or 30-70 years old, or 40-80 years old, or 40-60 years    old, or 40-70 years old, or 50-80 years old, or 50-70 years old.-   1.20 The composition for use of any of the preceding items, wherein    the patient suffers from a co-morbidity, for example,    conjunctivitis, stye, chalazion, blepharitis, ectropion, eyelid    laxity, eyelid edema, eyelid dermatitis, punctate keratopathy, or    ocular allergies, or any combination thereof.-   1.21 The composition for use of any of the preceding items, wherein    the patient suffers from keratoconjunctivitis sicca which is caused    by treatment of a co-morbidity, for example, treatment with any one    or more of: isotretinoin, sedatives, diuretics, tricyclic    antidepressants, antihypertensives, anticholinergics, oral    contraceptives, antihistamine, nasal decongestants, beta-adrenergic    antagonists, phenothiazines, atropine opiates (e.g., morphine),    optionally wherein any such treatment is concurrent or previous, and    further optionally, wherein any such treatment is systemic (e.g.,    oral or parenteral).-   1.22 The composition for use of any of the preceding items, wherein    the patient suffers from keratoconjunctivitis sicca which is caused    by ocular surgical intervention, for example, corneal surgery,    refractive surgery, LASIK surgery, cataract surgery, optionally    wherein any such ocular surgery is concurrent or previous.-   1.23 The composition for use of any of the preceding items, wherein    the patient is concomitantly under treatment with another topical    ophthalmic medication, for example, an antibiotic, antifungal,    corticosteroid, another immunosuppressant, sympathomimetic,    anesthetic, antihistamine, or any combination thereof.-   1.24 The composition for use of any of the preceding items, wherein    the patient is a contact lens wearer.-   1.25 The composition for use of any of the preceding items, wherein    the patient was unresponsive or insufficiently response to previous    treatment for keratoconjunctivitis sicca (dry eye disease).-   1.26 The composition for use of 1.25, wherein said previous    treatment comprises one or more of the following treatment methods:    topical aqueous immunosuppressant administration, (e.g., topical    aqueous ciclosporin), topical corticosteroid administration, or    topical aqueous artificial tears administration.-   1.27 The composition for use of any of the preceding items, wherein    the patient has at least one eye with a total corneal fluorescein    staining score at least equal or higher than 10.-   1.28 The composition for use of any of the preceding items, wherein    the patient has at least one eye with any one or combination of    criteria (e.g. signs of dry eye disease) selected from the group    consisting of:    -   i. A total lissamine green conjunctival score (sum of temporal        and nasal regions) of ≥2 according to the Oxford scale;    -   ii. a total corneal fluorescein staining (NEI scale) of ≥10        (i.e. sum of inferior, superior, central, nasal and temporal        regions);    -   iii. an unanesthetized Schirmer's Test score between 1 mm and 10        mm.-   1.29 The composition for use according to item 1.28, wherein the    patient has at least one eye (i.e. the same eye) which meets    criteria (i), (ii) and (iii).-   1.30 The composition for use according to any one of the preceding    items, wherein the patient has at least one eye, or both eyes with    any one or combination of:    -   i. a central corneal fluorescein staining (NEI scale) score of 2        or higher,    -   ii. an inferior corneal fluorescein staining (NEI scale) score        of 2 or higher,    -   iii. a total corneal fluorescein staining (NEI scale) score of        11 or higher.-   1.31 The composition for use of any of the preceding items, wherein    the patient has a history of keratoconjunctivitis sicca (dry eye    disease) in one or both eyes for at least six months.-   1.32 The composition for use of any of the preceding items, wherein    the composition is effective in reducing one or more signs and/or    symptoms of keratoconjunctivitis sicca (dry eye disease), preferably    wherein the one or more signs and/or symptoms is selected from    ocular surface damage.-   1.33 The composition for use of any of the preceding items, wherein    the composition is effective in reducing the one or more signs    and/or symptoms of keratoconjunctivitis sicca (dry eye disease)    within 2 weeks, within 4 weeks, or within 8 weeks after first    administration of the composition/commencement of treatment.-   1.34 The composition for use in in any of the preceding items,    wherein the composition is effective in reducing ocular surface    damage.-   1.35 The composition for use according to 1.32 to 1.34, wherein the    ocular surface damage is selected from the group consisting of:    -   i. surface damage of the total corneal region;    -   ii. surface damage of the central corneal region;    -   iii. surface damage of the nasal corneal region;    -   iv. surface damage of the temporal corneal region;    -   v. surface damage of the inferior corneal region; and    -   vi. combinations thereof.-   1.36 The composition for use of 1.35, wherein the ocular surface    damage is selected from ocular surface damage in the central corneal    region and ocular surface damage of the inferior corneal region.-   1.37 The composition for use of 1.32 to 1.36 wherein the reduction    of ocular surface damage is determined by corneal fluorescein    staining (NEI scale).-   1.38 The composition for use of 1.37, wherein the corneal    fluorescein staining method is selected from the group consisting    of:    -   iv. total corneal fluorescein staining;    -   v. central corneal fluorescein staining;    -   vi. nasal corneal fluorescein staining;    -   vii. temporal fluorescein staining;    -   viii. inferior corneal fluorescein staining; and    -   ix. any combination thereof.-   1.39 The composition for use of 1.32 to 1.38, wherein the treatment    is effective in reducing the total corneal fluorescein staining    score (sum of inferior, superior, central, nasal, and temporal    staining scores; NEI scale) by an integer of at least 2, or by at    least 3 points, optionally within a treatment period of at least 8    weeks, or at least 12 weeks.-   1.40 The composition for use of any of the preceding items, wherein    the composition is effective in treating one or more ocular symptoms    of keratoconjunctivitis sicca (dry eye disease) selected from (x)    dryness, (xi) sticky feeling, (xii) burning/stinging, (xiii) foreign    body sensation, (xiv) itching, (xv) blurred vision, (xvi)    sensitivity to light, (xvii) pain, and (xviii) any combination    thereof.-   1.41 The composition for use of any of the preceding items, wherein    the composition is effective in reducing the (xix) frequency of    dryness, (xx) awareness of symptoms of dry eye and (xxi) the    severity of dryness and (xxi) any combination thereof.-   1.42 The composition for use of item 1.41, wherein the composition    is effective in reducing the severity of dryness or the frequency of    dryness or the combination thereof.-   1.43 The composition for use of any preceding items, wherein the    method of treatment comprises the reduction of ocular surface    damage, e.g. ocular surface damage of the cornea, or ocular surface    damage selected from: i. surface damage of the total corneal    region; ii. surface damage of the central corneal region; iii.    surface damage of the nasal corneal region; iv. surface damage of    the temporal corneal region; v. surface damage of the inferior    corneal region; and vi. combinations thereof-   1.44 The composition for use of item 1.43, wherein the ocular    surface damage is selected from ocular surface damage in the central    corneal region and ocular surface damage of the inferior corneal    region.-   1.45 The composition for use of item 1.43-1.44 wherein the ocular    surface damage is determined by corneal fluorescein staining (NEI    scale).-   1.46 The composition for use of any of the preceding items, wherein    the patient has at least one eye with any one or combination of    criteria selected from the group consisting of:    -   a total corneal fluorescein staining value in the range of 10 to        15, preferably 10 to 13 (NEI scale);    -   a central corneal fluorescein staining value in the range of 1        to 3 (NEI scale); preferably 2 to 3 (NEI scale);    -   a total lissamine green conjunctival staining score in the range        of 2 to 6, preferably 3 to 5;    -   an unanesthetized Schirmer's test score in the range of 2 to 8        mm.-   1.47 The composition for use of any of the preceding items, wherein    the patient does not suffer from meibomian gland dysfunction and/or    blepharitis.-   1.48 The composition for use of any of the preceding items, wherein    the patient has an unanesthetized Schirmer's Test score in the range    of 3 to 7 mm, preferably in the range of 4 to 6 mm, more preferably    of about 5 mm.-   1.49 The composition for use of any of the preceding items, wherein    the patient has at least one eye with a total corneal fluorescein    staining score at least equal or higher than 11 (NEI scale).-   1.50 The composition for use of any of the preceding items, wherein    the patient has at least one eye with a central corneal fluorescein    staining value in the range of 1 to 3 (NEI scale).-   1.51 The composition for use of any of the preceding items, wherein    the patient has at least one eye with a total lissamine green    conjunctival staining score in the range of 2 to 6.-   1.52 The composition for use of any of the preceding items, wherein    the patient has at least one eye with an unanesthetized Schirmer's    test score in the range of 4 to 6 mm.-   1.53 The composition for use of any of the preceding items, wherein    the central corneal fluorescein staining value is about 3 (NEI    scale).-   1.54 The composition for use of any of the preceding items, wherein    the lissamine green conjunctival staining score is in the range of 3    to 5.-   1.55 The composition for use of any of the preceding items, wherein    the unanesthetized Schirmer's test score is about 5 mm.-   1.56 An ophthalmic composition comprising 0.1% (w/v) cyclosporine    dissolved in 1-(perfluorobutyl)pentane for use in a method of    treating keratoconjunctivitis sicca (dry eye disease), wherein the    method comprises a step of topically administering the composition    to an eye of a patient, wherein the patient has at least one eye    with a total corneal fluorescein staining score at least equal or    higher than 11 (NEI scale).-   1.57 An ophthalmic composition comprising 0.1% (w/v) cyclosporine    dissolved in 1-(perfluorobutyl)pentane for use in a method of    treating keratoconjunctivitis sicca (dry eye disease), wherein the    method comprises a step of topically administering the composition    to an eye of a patient, wherein the patient has a total ocular    surface disease index (OSDI) score of equal or greater than 45, and    wherein the patient has at least one eye with a total corneal    fluorescein staining score at least equal or higher than 11 (NEI    scale).-   1.58 An ophthalmic composition comprising 0.1% (w/v) cyclosporine    dissolved in 1-(perfluorobutyl)pentane for use in a method of    treating keratoconjunctivitis sicca (dry eye disease), wherein the    method comprises a step of topically administering the composition    to an eye of a patient, wherein the patient has a total ocular    surface disease index (OSDI) score of equal or greater than 45, and    wherein the patient has at least one eye with:    -   a total corneal fluorescein staining score at least equal or        higher than 11 (NEI scale); and    -   a central corneal fluorescein staining value in the range of 1        to 3 (NEI scale).-   1.59 An ophthalmic composition comprising 0.1% (w/v) cyclosporine    dissolved in 1-(perfluorobutyl)pentane for use in a method of    treating keratoconjunctivitis sicca (dry eye disease), wherein the    method comprises a step of topically administering the composition    to an eye of a patient, wherein the patient has a total ocular    surface disease index (OSDI) score of equal or greater than 45, and    wherein the patient has at least one eye with:    -   a total corneal fluorescein staining score at least equal or        higher than 11 (NEI scale);    -   a central corneal fluorescein staining value in the range of 1        to 3 (NEI scale); and    -   a total lissamine green conjunctival staining score in the range        of 2 to 6.-   1.60 An ophthalmic composition comprising 0.1% (w/v) cyclosporine    dissolved in 1-(perfluorobutyl)pentane for use in a method of    treating keratoconjunctivitis sicca (dry eye disease), wherein the    method comprises a step of topically administering the composition    to an eye of a patient, wherein the patient has a total ocular    surface disease index (OSDI) score of equal or greater than 45, and    wherein the patient has at least one eye with:    -   a total corneal fluorescein staining score at least equal or        higher than 11 (NEI scale);    -   a central corneal fluorescein staining value in the range of 1        to 3 (NEI scale);    -   a total lissamine green conjunctival staining score in the range        of 2 to 6; and    -   an unanesthetized Schirmer's test score in the range of 4 to 6        mm.-   1.61 The composition for use in any one of items 1.58 to 1.60,    wherein the central corneal fluorescein staining value is about 3    (NEI scale).-   1.62 The composition for use in any one of items 1.59 to 1.61,    wherein the lissamine green conjunctival staining score is in the    range of 3 to 5.-   1.63 The composition for use in any one of items 1.60 to 1.62,    wherein the unanesthetized Schirmer's test score is about 5 mm.-   1.64 The composition for use in any one of items 1.57 to 1.63,    wherein the patient has a total ocular surface disease index (OSDI)    score of equal or greater than 55.-   1.65 The composition for use in any one of items 1.49 to 1.64,    wherein the patient has the total corneal flueorescein staining    score, the central corneal fluorescein staining value, the lissamine    green conjunctival staining score, and/or the unanesthetized    Schirmer's test score with the specified values in both eyes.

In a second aspect the present disclosure may relate to a method oftreatment according to the following:

-   2.1 A method of treating keratoconjunctivitis sicca (dry eye    disease) comprising a step of topically administering an ophthalmic    composition comprising 0.1% (w/v) cyclosporine dissolved in    1-(perfluorobutyl)pentane to an eye of a patient, wherein the    patient has a total ocular surface disease index (OSDI) score of    equal or greater than 45.-   2.2 Method 2.1, wherein the patient has a total ocular surface    disease index (OSDI) score of equal or greater than 55.-   2.3 Any preceding method, wherein the composition comprises up to    about 1.0% (w/w) ethanol.-   2.4 Any preceding method, wherein the composition consists of about    0.1% (w/v) cyclosporine, F4H5 and up to about 1.0% (w/w) ethanol.-   2.5 Any preceding method, wherein the ophthalmic composition is    administered to the surface of the cornea and/or conjunctiva in the    form of a liquid drop.-   2.6 Any preceding method, wherein the composition is administered as    a single drop having a volume of about 8 to 11 μL, preferably of    about 8 to 10 μL.-   2.7 Any preceding method, wherein the composition is administered in    a dose of a single drop per eye one time per day in volume of 8-10    μL.-   2.8 Any preceding method, wherein the composition is administered as    a single drop having a volume of about 10 μl.-   2.9 Any preceding method, wherein the composition is administered    twice per day per eye.-   2.10 Any preceding method, wherein the composition is administered    in a dose of a single drop per eye twice per day in net volume of    about 16-20 μL.-   2.11 Any preceding method, wherein the dry eye disease is    aqueous-deficient dry eye disease.-   2.12 Any preceding method, wherein the dry eye disease is    evaporative dry eye disease.-   2.13 Any preceding method, wherein the patient is non-responsive, or    insufficiently responsive to treatment with aqueous ophthalmic eye    drop compositions (e.g. aqueous cyclosporin emulsion eye drops).-   2.14 Any preceding method, wherein the time interval between topical    administration of the composition to the eye or eye surface of a    first dose and a second dose is at least 4 hours, or at least 6    hours, or at least 12 hours.-   2.15 Any preceding method, wherein the duration of the treatment is    for at at least 2 weeks, or at least 4 weeks, or at least 6 weeks,    or at least 8 weeks, or at least 12 weeks.-   2.16 Any preceding method, wherein the patient is a human patient.-   2.17 Any preceding method, wherein the patient is a female patient.-   2.18 Any preceding method, wherein the patient is a male patient.-   2.19 Any preceding method, wherein the patient is aged 20-80 years    old at the time of treatment, e.g., 20-50 years old, or 20-70 years    old, or 30-80 years old, or 30-50 years old, or 30-70 years old, or    40-80 years old, or 40-60 years old, or 40-70 years old, or 50-80    years old, or 50-70 years old.-   2.20 Any preceding method, wherein the patient suffers from a    co-morbidity, for example, conjunctivitis, stye, chalazion,    blepharitis, ectropion, eyelid laxity, eyelid edema, eyelid    dermatitis, punctate keratopathy, or ocular allergies, or any    combination thereof.-   2.21 Any preceding method, wherein the patient suffers from    keratoconjunctivitis sicca which is caused by treatment of a    co-morbidity, for example, treatment with any one or more of:    isotretinoin, sedatives, diuretics, tricyclic antidepressants,    antihypertensives, anticholinergics, oral contraceptives,    antihistamine, nasal decongestants, beta-adrenergic antagonists,    phenothiazines, atropine opiates (e.g., morphine), optionally    wherein any such treatment is concurrent or previous, and further    optionally, wherein any such treatment is systemic (e.g., oral or    parenteral).-   2.22 Any preceding method, wherein the patient suffers from    keratoconjunctivitis sicca which is caused by ocular surgical    intervention, for example, corneal surgery, refractive surgery,    LASIK surgery, cataract surgery, optionally wherein any such ocular    surgery is concurrent or previous.-   2.23 Any preceding method, wherein the patient is concomitantly    under treatment with another topical ophthalmic medication, for    example, an antibiotic, antifungal, corticosteroid, another    immunosuppressant, sympathomimetic, anesthetic, antihistamine, or    any combination thereof.-   2.24 Any preceding method, wherein the patient is a contact lens    wearer.-   2.25 Any preceding method, wherein the patient was unresponsive or    insufficiently response to previous treatment for    keratoconjunctivitis sicca (dry eye disease).-   2.26 Method 2.25, wherein said previous treatment comprise one or    more of the following treatment methods: topical aqueous    immunosuppressant administration, (e.g., topical aqueous    ciclosporin), topical corticosteroid administration, or topical    aqueous artificial tears administration.-   2.27 Any preceding method, wherein the patient has at least one eye    with a total corneal fluorescein staining score of at least equal or    higher than 10.-   2.28 Any preceding method, wherein the patient has at least one eye    with any one or combination of criteria (e.g. signs of dry eye    disease) selected from the group consisting of:    -   i. A total lissamine green conjunctival score (sum of temporal        and nasal regions) of 2 according to the Oxford scale;    -   ii. a total corneal fluorescein staining (NEI scale) of 10 (i.e.        sum of inferior, superior, central, nasal and temporal regions);    -   iii. an unanesthetized Schirmer's Test score between 1 mm and 10        mm.-   2.29 Method 2.28, wherein the patient has at least one eye (i.e. the    same eye) which meets criteria (i), (ii) and (iii).-   2.30 Any preceding method, wherein the patient has at least one eye,    or both eyes with any one or combination of:    -   i. a central corneal fluorescein staining (NEI scale) score of 2        or higher,    -   ii. an inferior corneal fluorescein staining (NEI scale) score        of 2 or higher,    -   iii. a total corneal fluorescein staining (NEI scale) score of        11 or higher.-   2.31 Any preceding method, wherein the patient has a history of    keratoconjunctivitis sicca (dry eye disease) in one or both eyes for    at least six months.-   2.32 Any preceding method, wherein the composition is effective in    reducing one or more signs and/or symptoms of keratoconjunctivitis    sicca (dry eye disease), preferably wherein the one or more signs    and/or symptoms is selected from ocular surface damage.-   2.33 Any preceding method, wherein the composition is effective in    reducing the one or more signs and/or symptoms of    keratoconjunctivitis sicca (dry eye disease) within 2 weeks, within    4 weeks, or within 8 weeks after first administration of the    composition/commencement of treatment.-   2.34 Any preceding method, wherein the composition is effective in    reducing ocular surface damage.-   2.35 Method 2.32 to 2.34, wherein the ocular surface damage is    selected from the group consisting of:    -   i. surface damage of the total corneal region;    -   ii. surface damage of the central corneal region;    -   iii. surface damage of the nasal corneal region;    -   iv. surface damage of the temporal corneal region;    -   v. surface damage of the inferior corneal region; and    -   vi. combinations thereof.-   2.36 Method 2.35, wherein the ocular surface damage is selected from    ocular surface damage in the central corneal region and ocular    surface damage of the inferior corneal region.-   2.37 Method 2.32 to 2.36 wherein the reduction of ocular surface    damage is determined by corneal fluorescein staining (NEI scale).-   2.38 Method 2.37, wherein the corneal fluorescein staining method is    selected from the group consisting of:    -   iv. total corneal fluorescein staining;    -   v. central corneal fluorescein staining;    -   vi. nasal corneal fluorescein staining;    -   vii. temporal fluorescein staining;    -   viii. inferior corneal fluorescein staining; and    -   ix. any combination thereof.-   2.39 Method 2.32 to 2.38, wherein the treatment is effective in    reducing the total corneal fluorescein staining score (sum of    inferior, superior, central, nasal, and temporal staining scores;    NEI scale) by an integer of at least 2, or by at least 3 points,    optionally within a treatment period of at least 8 weeks, or at    least 12 weeks.-   2.40 Any preceding method, wherein the composition is effective in    treating one or more ocular symptoms of keratoconjunctivitis sicca    (dry eye disease) selected from (x) dryness, (xi) sticky    feeling, (xii) burning/stinging, (xiii) foreign body    sensation, (xiv) itching, (xv) blurred vision, (xvi) sensitivity to    light, (xvii) pain, (xviii) and any combination thereof.-   2.41 Any preceding method, wherein the composition is effective in    reducing the (xix) frequency of dryness, (xx) awareness of symptoms    and (xxi) the severity of dryness and (xxi) any combination thereof.-   2.42 Method 2.40 to 2.41, wherein the composition is effective in    reducing the severity of dryness or the frequency of dryness or the    combination thereof.-   2.43 Any preceding method, wherein the method of treatment comprises    the reduction of ocular surface damage, e.g. ocular surface damage    of the cornea, or ocular surface damage selected from: i. surface    damage of the total corneal region; ii. surface damage of the    central corneal region; iii. surface damage of the nasal corneal    region; iv. surface damage of the temporal corneal region; v.    surface damage of the inferior corneal region; and vi. combinations    thereof.-   2.44 Method 2.43, wherein the ocular surface damage is selected from    ocular surface damage in the central corneal region and ocular    surface damage of the inferior corneal region.-   2.45 Method 2.43 to 2.44 wherein the ocular surface damage is    determined by corneal fluorescein staining (NEI scale).-   2.46 Any preceding method, wherein the patient has at least one eye    with any one or combination of criteria selected from the group    consisting of:    -   a total corneal fluorescein staining value in the range of 10 to        15, preferably 10 to 13 (NEI scale);    -   a central corneal fluorescein staining value in the range of 1        to 3 (NEI scale);    -   preferably 2 to 3 (NEI scale);    -   a total lissamine green conjunctival staining score in the range        of 2 to 6, preferably 3 to 5;    -   an unanesthetized Schirmer's test score in the range of 2 to 8        mm.-   2.47 Any preceding method, in which the patient does not suffer from    blepharitis and/or meibomian gland dysfunction.-   2.48 Any preceding method, wherein the patient has an unanesthetized    Schirmer's Test score in the range of 3 to 7 mm, preferably in the    range of 4 to 6 mm, more preferably of about 5 mm.-   2.49 Any preceding method, wherein the patient has at least one eye    with a total corneal fluorescein staining score at least equal or    higher than 11 (NEI scale).-   2.50 Any preceding method, wherein the patient has at least one eye    with a central corneal fluorescein staining value in the range of 1    to 3 (NEI scale).-   2.51 Any preceding method, wherein the patient has at least one eye    with a total lissamine green conjunctival staining score in the    range of 2 to 6.-   2.52 Any preceding method, wherein the patient has at least one eye    with an unanesthetized Schirmer's test score in the range of 4 to 6    mm.-   2.53 Any preceding method, wherein the central corneal fluorescein    staining value is about 3 (NEI scale).-   2.54 Any preceding method, wherein the lissamine green conjunctival    staining score is in the range of 3 to 5.-   2.55 Any preceding method, wherein the unanesthetized Schirmer's    test score is about 5 mm.-   2.56 A method of treating keratoconjunctivitis sicca (dry eye    disease) comprising a step of topically administering an ophthalmic    composition comprising 0.1% (w/v) cyclosporine dissolved in    1-(perfluorobutyl)pentane to an eye of a patient, wherein the    patient has at least one eye with a total corneal fluorescein    staining score at least equal or higher than 11 (NEI scale).-   2.57 A method of treating keratoconjunctivitis sicca (dry eye    disease) comprising a step of topically administering an ophthalmic    composition comprising 0.1% (w/v) cyclosporine dissolved in    1-(perfluorobutyl)pentane to an eye of a patient, wherein the    patient has a total ocular surface disease index (OSDI) score of    equal or greater than 45, and wherein the patient has at least one    eye with a total corneal fluorescein staining score at least equal    or higher than 11 (NEI scale).-   2.58 A method of treating keratoconjunctivitis sicca (dry eye    disease) comprising a step of topically administering an ophthalmic    composition comprising 0.1% (w/v) cyclosporine dissolved in    1-(perfluorobutyl)pentane to an eye of a patient, wherein the    patient has a total ocular surface disease index (OSDI) score of    equal or greater than 45, and wherein the patient has at least one    eye with:    -   a total corneal fluorescein staining score at least equal or        higher than 11 (NEI scale); and    -   a central corneal fluorescein staining value in the range of 1        to 3 (NEI scale).-   2.59 A method of treating keratoconjunctivitis sicca (dry eye    disease) comprising a step of topically administering an ophthalmic    composition comprising 0.1% (w/v) cyclosporine dissolved in    1-(perfluorobutyl)pentane to an eye of a patient, wherein the    patient has a total ocular surface disease index (OSDI) score of    equal or greater than 45, and wherein the patient has at least one    eye with:    -   a total corneal fluorescein staining score at least equal or        higher than 11 (NEI scale);    -   a central corneal fluorescein staining value in the range of 1        to 3 (NEI scale); and    -   a total lissamine green conjunctival staining score in the range        of 2 to 6.-   2.60 A method of treating keratoconjunctivitis sicca (dry eye    disease) comprising a step of topically administering an ophthalmic    composition comprising 0.1% (w/v) cyclosporine dissolved in    1-(perfluorobutyl)pentane to an eye of a patient, wherein the    patient has a total ocular surface disease index (OSDI) score of    equal or greater than 45, and wherein the patient has at least one    eye with:    -   a total corneal fluorescein staining score at least equal or        higher than 11 (NEI scale);    -   a central corneal fluorescein staining value in the range of 1        to 3 (NEI scale);    -   a total lissamine green conjunctival staining score in the range        of 2 to 6; and    -   an unanesthetized Schirmer's test score in the range of 4 to 6        mm.-   2.61 Method 2.58 to 2.60, wherein the central corneal fluorescein    staining value is about 3 (NEI scale).-   2.62 Method 2.59 to 2.61, wherein the lissamine green conjunctival    staining score is in the range of 3 to 5.-   2.63 Method 2.60 to 2.62, wherein the unanesthetized Schirmer's test    score is about 5 mm.-   2.64 Method 2.57 to 2.63, wherein the patient has a total ocular    surface disease index (OSDI) score of equal or greater than 55.-   2.65 Method 2.49 to 2.64, wherein the patient has the total corneal    flueorescein staining score, the central corneal fluorescein    staining value, the lissamine green conjunctival staining score,    and/or the unanesthetized Schirmer's test score with the specified    values in both eyes.

In a third aspect, the present invention provides for the followingitems:

-   3.1 An ophthalmic composition comprising 0.1% (w/v) cyclosporine    dissolved in 1-(perfluorobutyl) pentane for use in:    -   a) a method of treating and/or ameliorating the symptoms        associated with keratoconjunctivitis sicca (dry eyes), wherein        the symptoms are dryness (severity of dryness) and blurred        vision;    -   and/or    -   b) a method of treating and/or ameliorating the awareness of        symptoms of dry eyes and the frequency of dryness, preferably        wherein the symptoms of dry eyes are selected from dryness,        sticky feeling, burning/stinging, foreign body sensation,        itching, blurred vision, sensitivity to light, and pain in the        eyes of a patient.-   3.2 The composition for use of 3.1, wherein the composition is    topically administered to the eye of a patient.-   3.3 The composition for use according to 3.1 or 3.2, wherein the    dryness (severity of dryness), the blurred vision, the frequency of    dryness and the awareness of symptoms of dry eyes are determined on    a visual analog scale (VAS) on a scale of 0% to 100%, wherein for    frequency of dryness and awareness of dry eyes symptoms the scale of    0% to 100% is the percentage of time dryness and dry eyes symptoms    are experienced by a patient and wherein for dryness and blurred    vision the scale of 0% to 100% is the percentage level of discomfort    experienced by a patient.-   3.4 The composition for use of any one of the preceding items,    wherein the composition comprises up to about 1.0% (w/w) ethanol.-   3.5 The composition for use of any one of the preceding items,    wherein the composition consists of about 0.1% (w/v) cyclosporine,    1-perfluorobutylpentane (F4H5) and up to about 1.0% (w/w) ethanol.-   3.6 The composition for use of any of the preceding items, wherein    the ophthalmic composition is administered to the surface of the    cornea and/or conjunctiva in the form of a liquid drop.-   3.7 The composition for use in any of the preceding items, wherein    the composition is administered as a single drop having a volume of    about 8 to 11 μL, preferably of about 8 to 10 μL.-   3.8 The composition for use of any of the preceding items, wherein    the composition is administered in a dose of a single drop per eye    in volume of about 8 to 10 μL.-   3.9 The composition for use according to any one of the preceding    claims, wherein the composition is administered as a single drop    having a volume of about 10 μl.-   3.10 The ophthalmic composition for use of any one of the preceding    items, wherein the composition is administered twice per day per    eye.-   3.11 The composition for use in any of the preceding items, wherein    the composition is administered in a dose of a single drop per eye    twice per day in net volume of about 16-20 μL.-   3.12 The composition for use according to any one of the preceding    items, wherein the dry eye disease is aqueous-deficient dry eye    disease.-   3.13 The composition for use according to any of the preceding    items, wherein the dry eye disease is evaporative dry eye disease.-   3.14 The composition for use in according to any of the preceding    items, wherein the patient is non-responsive, or insufficiently    responsive, to treatment with aqueous ophthalmic eye drop    compositions.-   3.15 The composition for use of any of the preceding items, wherein    the time interval between topical administration of the composition    to the eye or eye surface of a first dose and a second dose is at    least 4 hours, or at least 6 hours, or at least 12 hours.-   3.16 The composition for use of any of the preceding items, wherein    the duration of the treatment is for at least 2 weeks, or at least 4    weeks, or at least 6 weeks, or at least 8 weeks, or at least 12    weeks.-   3.17 The composition for use of any of the preceding items wherein    the patient is a human patient.-   3.18 The composition for use of any of the preceding items, wherein    the patient is a female patient.-   3.19 The composition for use of any of the preceding items, wherein    the patient is a male patient.-   3.20 The composition for use of any of the preceding items, wherein    the patient is aged 20-80 years old at the time of treatment, e.g.,    20-50 years old, or 20-70 years old, or 30-80 years old, or 30-50    years old, or 30-70 years old, or 40-80 years old, or 40-60 years    old, or 40-70 years old, or 50-80 years old, or 50-70 years old.-   3.21 The composition for use of any of the preceding items, wherein    the patient suffers from a co-morbidity, for example,    conjunctivitis, stye, chalazion, blepharitis, ectropion, eyelid    laxity, eyelid edema, eyelid dermatitis, punctate keratopathy, or    ocular allergies, or any combination thereof.-   3.22 The composition for use of any of the preceding items, wherein    the patient suffers from keratoconjunctivitis sicca which is caused    by treatment of a co-morbidity, for example, treatment with any one    or more of: isotretinoin, sedatives, diuretics, tricyclic    antidepressants, antihypertensives, anticholinergics, oral    contraceptives, antihistamine, nasal decongestants, beta-adrenergic    antagonists, phenothiazines, atropine opiates (e.g., morphine),    optionally wherein any such treatment is concurrent or previous, and    further optionally, wherein any such treatment is systemic (e.g.,    oral or parenteral).-   3.23 The composition for use of any of the preceding items, wherein    the patient suffers from keratoconjunctivitis sicca which is caused    by ocular surgical intervention, for example, corneal surgery,    refractive surgery, LASIK surgery, cataract surgery, optionally    wherein any such ocular surgery is concurrent or previous.-   3.24 The composition for use of any of the preceding items, wherein    the patient is concomitantly under treatment with another topical    ophthalmic medication, for example, an antibiotic, antifungal,    corticosteroid, another immunosuppressant, sympathomimetic,    anesthetic, antihistamine, or any combination thereof.-   3.25 The composition for use of any of the preceding items, wherein    the patient is a contact lens wearer.-   3.26 The composition for use of any of the preceding items, wherein    the patient was unresponsive or insufficiently responsive to    previous treatment for keratoconjunctivitis sicca (dry eye disease).-   3.27 The composition for use in 3.26, wherein said previous    treatment comprise one or more of the following treatment methods:    topical aqueous immunosuppressant administration (e.g., topical    aqueous ciclosporin), topical corticosteroid administration, or    topical aqueous artificial tears administration.-   3.28 The composition for use of any of the preceding items, wherein    the patient has at least one eye with any one, or combination of    criteria (e.g. signs of dry eye disease) selected from the group    consisting of:    -   i. A total lissamine green conjunctival score (sum of temporal        and nasal regions) of 2 according to the Oxford scale;    -   ii. a total corneal fluorescein staining (NEI scale) of 10 (i.e.        sum of inferior, superior, central, nasal and temporal regions);        and    -   iii. an unanesthetized Schirmer's Test score between 1 mm and 10        mm;    -   and/or    -   wherein the patient has a total ocular surface disease index        score (OSDI) of equal or greater than 20.-   3.29 The composition for use according to any of the preceding    items, wherein the patient has a total ocular surface disease index    score (OSDI) of equal or greater than 45.-   3.30 The composition for use according to any of the preceding    items, wherein the patient has a total ocular surface disease index    score (OSDI) of equal or greater than 55.-   3.31 The composition for use according to item 3.28 to 3.30, wherein    the patient has at least one eye (i.e. the same eye) which meets all    of criteria (i), (ii), and (iii).-   3.32 The composition for use of any of the preceding items, wherein    the patient has a history of keratoconjunctivitis sicca (dry eye    disease) in one or both eyes for at least six months.-   3.33 The composition for use of any of the preceding items, wherein    the composition is effective in reducing one or more signs and/or    symptoms of keratoconjunctivitis sicca (dry eye disease), preferably    wherein the signs and/or symptoms is selected from ocular surface    damage.-   3.34 The composition for use of any of the preceding items, wherein    the composition is effective in reducing one or more signs and/or    symptoms of keratoconjunctivitis sicca (dry eye disease) within 2    weeks, or within 4 weeks, or within 8 weeks after first    administration of the composition.-   3.35 The composition for use in in any of the preceding items,    wherein the composition is effective in reducing ocular surface    damage.-   3.36 The composition for use according to item 3.35, wherein the    ocular surface damage is selected from the group consisting of:    -   i. surface damage of the total corneal region;    -   ii. surface damage of the central corneal region;    -   iii. surface damage of the nasal corneal region;    -   iv. surface damage of the temporal corneal region;    -   v. surface damage of the inferior corneal region; and    -   vi. combinations thereof.-   3.37 The composition for use of item 3.36, wherein the ocular    surface damage is selected from ocular surface damage in the central    corneal region and ocular surface damage of the inferior corneal    region.-   3.38 The composition for use of item 3.35 to 3.37 wherein the    reduction of ocular surface damage is determined by corneal    fluorescein staining (NEI scale).-   3.39 The composition for use in item 3.38, wherein the corneal    fluorescein staining method is selected from the group consisting    of:    -   iv. total corneal fluorescein staining;    -   v. central corneal fluorescein staining;    -   vi. nasal corneal fluorescein staining;    -   vii. temporal fluorescein staining;    -   viii. inferior corneal fluorescein staining; and    -   ix. any combination thereof.-   3.40 The composition for use of any of the preceding items, wherein    the composition is effective in reducing the frequency of dryness    and/or the awareness of dry eye symptoms and/or the severity of    dryness and any combination thereof.-   3.41 The composition for use of item 3.40, wherein the composition    is effective in reducing the frequency of dryness and/or the    awareness of dry eye symptoms and/or the severity of dryness, or any    combination thereof, within 2 weeks after start of treatment, or    within 4 weeks after start of treatment.-   3.42 The composition for use of item 3.40 or 3.41 wherein the    composition is effective in reducing the frequency of dryness and/or    the severity of dryness by at least 25%, preferably by at least 30%    after two weeks or after four weeks or after 8 weeks or after 12    weeks of treatment.-   3.43 The composition for use of item 3.40 to 3.42, wherein the    composition is effective in reducing the severity of dryness and/or    the frequency of dryness by at least 25% in more than at least 20%    of patients undergoing treatment after two weeks of treatment; or in    more than 30% of patients undergoing treatment after four weeks of    treatment; or in more than at least 35% of patients under going    treatment after eight weeks of treatment.-   3.44 The composition for use of items 3.40 to 3.43, wherein the    effectiveness of the composition for use is determined by visual    analog scale (VAS) testing on a scale of 0 to 100%, wherein    frequency of dryness and awareness of dry eye symptoms are measured    on a scale of 0 to 100% as the percentage of time said symptom(s) is    experienced by a patient and wherein the severity of dryness is    measured on a scale of 0 to 100% as the percentage level of    discomfort experienced by the patient.-   3.45 The composition for use of any preceding item, wherein the    method of treatment comprises reducing ocular surface damage, e.g.    ocular surface damage of the cornea, or ocular surface damage    selected from i. surface damage of the total corneal region; ii.    surface damage of the central corneal region; iii. surface damage of    the nasal corneal region; iv. surface damage of the temporal corneal    region; v. surface damage of the inferior corneal region; and vi.    combinations thereof.-   3.46 The composition for use of item 3.45, wherein the ocular    surface damage is selected from ocular surface damage in the central    corneal region and ocular surface damage of the inferior corneal    region.-   3.47 The composition for use of item 3.45 to 3.46 wherein the ocular    surface damage is determined by corneal fluorescein staining (NEI    scale).-   3.48 The composition for use of any of the preceding items, wherein    patient has at least one eye with any one or combination of criteria    selected from the group consisting of:    -   a total corneal fluorescein staining value in the range of 10 to        15, preferably 10 to 13 (NEI scale);    -   a central corneal fluorescein staining value in the range of 1        to 3 (NEI scale); preferably 2 to 3 (NEI scale);    -   a total lissamine green conjunctival staining score in the range        of 2 to 6, preferably 3 to 5;    -   an unanesthetized Schirmer's test score in the range of 2 to 8        mm;    -   a total OSDI score in the range of 25 to 64, preferably 30 to        64.-   3.49 The composition for use of any of the preceding items, wherein    the patient has an unanesthetized Schirmer's Test score in the range    of 3 to 7 mm, preferably in the range of 4 to 6 mm, more preferably    of about 5 mm.-   3.50 The composition for use of any of the preceding items, wherein    the composition is effective in reducing in a patient the total    corneal fluorescein staining score (sum of inferior, superior,    central, nasal, and temporal staining scores; NEI scale), by at    least 3 grades after 4 weeks of treatment, preferably in at least    50% of the patients undergoing treatment.-   3.51 The composition for use of any preceding items, wherein the    composition is effective in reducing the central corneal    fluoresceing staining score in a patient by at least 1 grade after    four weeks of treatment, preferably in at least 50% of the patients    undergoing treatment.-   3.52 The composition for use of any preceding items, wherein the    composition is effective in reducing the conjunctival lissamine    green staining (Oxford scale) in a patient by at least 2 grades    after four weeks or after twelve weeks of treatment, preferably in    at least 30% of the patients undergoing treatment after four weeks    of treatment or preferably in at least 50% of the patients after    twelve weeks of treatment.-   3.53 The composition for use of any of the preceding items, wherein    the patient does not suffer from meibomian gland dysfunction and/or    blepharitis.-   3.54 The composition for use of any of the preceding items, wherein    the patient has at least one eye with a total corneal fluorescein    staining score at least equal or higher than 11 (NEI scale).-   3.55 The composition for use of any of the preceding items, wherein    the patient has at least one eye with a central corneal fluorescein    staining value in the range of 1 to 3 (NEI scale).-   3.56 The composition for use of any of the preceding items, wherein    the patient has at least one eye with a total lissamine green    conjunctival staining score in the range of 2 to 6.-   3.57 The composition for use of any of the preceding items, wherein    the patient has at least one eye with an unanesthetized Schirmer's    test score in the range of 4 to 6 mm.-   3.58 The composition for use of any of the preceding items, wherein    the central corneal fluorescein staining value is about 3 (NEI    scale).-   3.59 The composition for use of any of the preceding items, wherein    the lissamine green conjunctival staining score is in the range of 3    to 5.-   3.60 The composition for use of any of the preceding items, wherein    the unanesthetized Schirmer's test score is about 5 mm.-   3.61 An ophthalmic composition comprising 0.1% (w/v) cyclosporine    dissolved in 1-(perfluorobutyl)pentane for use in:    -   a) a method of treating and/or ameliorating the symptoms        associated with keratoconjunctivitis sicca (dry eyes), wherein        the symptoms are dryness (severity of dryness) and blurred        vision;    -   and/or    -   b) a method of treating and/or ameliorating the awareness of        symptoms of dry eyes and the frequency of dryness, preferably        wherein the symptoms of dry eyes are selected from dryness,        sticky feeling, burning/stinging, foreign body sensation,        itching, blurred vision, sensitivity to light, and pain in the        eyes of a patient; wherein the composition is topically        administered to the eye of a patient, and wherein the patient        has at least one eye with a total corneal fluorescein staining        score at least equal or higher than 11 (NEI scale).-   3.62 The composition for use of item 3.61, wherein the patient has    at least one eye with a central corneal fluorescein staining value    in the range of 1 to 3 (NEI scale).-   3.63 The composition for use of item 3.61 or 3.62, wherein the    patient has at least one eye with a total lissamine green    conjunctival staining score in the range of 2 to 6.-   3.64 The composition for use of any one of items 3.61 to 3.63,    wherein the patient has at least one eye with an unanesthetized    Schirmer's test score in the range of 4 to 6 mm.-   3.65 The composition for use of any one of items 3.62 to 3.64,    wherein the central corneal fluorescein staining value is about 3    (NEI scale).-   3.66 The composition for use of any one of items 3.63 to 3.65,    wherein the lissamine green conjunctival staining score is in the    range of 3 to 5.-   3.67 The composition for use of any one of items 3.64 to 3.66,    wherein the unanesthetized Schirmer's test score is about 5 mm.-   3.68 The composition for use of any one of items 3.61 to 3.67,    wherein the patient has a total ocular surface disease index score    (OSDI) of equal or greater than 45.-   3.69 The composition for use of any one of items 3.61 to 3.68,    wherein the patient has a total ocular surface disease index score    (OSDI) of equal or greater than 55.-   3.70 The composition for use in any one of items 3.54 to 3.69,    wherein the patient has the total corneal flueorescein staining    score, the central corneal fluorescein staining value, the lissamine    green conjunctival staining score, and/or the unanesthetized    Schirmer's test score with the specified values in both eyes.

In a fourth aspect, the present invention provides for the followingmethod:

-   4.1 A method of treating and/or ameliorating the symptoms associated    with keratoconjunctivitis sicca (dry eyes) wherein the symptoms are    dryness (severity of dryness) and blurred vision, and wherein the    method comprises administering an ophthalmic composition comprising    0.1% (w/v) cyclosporine dissolved in 1-(perfluorobutyl)pentane to an    eye of a patient.-   4.2 Method 4.1 and/or a method of treating and/or ameliorating the    awareness of symptoms of dry eyes and the frequency of dryness,    preferably wherein the symptoms of dry eye are selected from    dryness, sticky feeling, burning/stinging, foreign body sensation,    itching, blurred vision, sensitivity to light, and pain, wherein    said method comprises administering an ophthalmic composition    comprising 0.1% (w/v) cyclosporine dissolved in    1-(perfluorobutyl)pentane to an eye of a patient.-   4.3 Method 4.1 or 4.2, wherein the composition is topically    administered to the eye of a patient.-   4.4 Method 4.1 to 4.3, wherein the dryness (severity of dryness),    the blurred vision, the frequency of dryness and the awareness of    symptoms of dry eyes are determined on a visual analog scale (VAS)    on a scale of 0% to 100%, wherein for frequency of dryness and    awareness of dry eyes symptoms the scale of 0% to 100% is the    percentage of time dryness and dry eyes symptoms are experienced by    a patient and wherein for dryness and blurred vision the scale of 0%    to 100% is the percentage level of discomfort experienced by a    patient.-   4.5 Any preceding method, wherein the composition comprises up to    about 1.0% (w/w) ethanol.-   4.6 Any preceding method, wherein the composition consists of about    0.1% (w/v) cyclosporine, 1-(perfluorobutyl)pentane (F4H5) and up to    about 1.0% (w/w) ethanol.-   4.7 Any preceding method, wherein the ophthalmic composition is    administered to the surface of the cornea and/or conjunctiva in the    form of a liquid drop.-   4.8 Any preceding method, wherein the composition is administered as    a single drop having a volume of about 8 to 11 μL, preferably of    about 8 to 10 μL.-   4.9 Any preceding method, wherein the composition is administered in    a dose of a single drop per eye in volume of about 8 to 10 μL.-   4.10 Any preceding method, wherein the composition is administered    as a single drop having a volume of about 10 μl.-   4.11 Any preceding method, wherein the composition is administered    twice per day per eye.-   4.12 Any preceding method, wherein the composition is administered    in a dose of a single drop per eye twice per day in net volume of    about 16-20 μL.-   4.13 Any preceding method, wherein the dry eye disease is    aqueous-deficient dry eye disease.-   4.14 Any preceding method, wherein the dry eye disease is    evaporative dry eye disease.-   4.15 Any preceding method, wherein the patient is non-responsive, or    insufficiently responsive, to treatment with aqueous ophthalmic eye    drop compositions.-   4.16 Any preceding method, wherein the time interval between topical    administration of the composition to the eye or eye surface of a    first dose and a second dose is at least 4 hours, or at least 6    hours, or at least 12 hours.-   4.17 Any preceding method, wherein the duration of the treatment is    for at least 2 weeks, or at least 4 weeks, or at least 6 weeks, or    at least 8 weeks, or at least 12 weeks.-   4.18 Any preceding method, wherein the patient is a human patient.-   4.19 Any preceding method, wherein the patient is a female patient.-   4.20 Any preceding method, wherein the patient is a male patient.-   4.21 Any preceding method, wherein the patient is aged 20-80 years    old at the time of treatment, e.g., 20-50 years old, or 20-70 years    old, or 30-80 years old, or 30-50 years old, or 30-70 years old, or    40-80 years old, or 40-60 years old, or 40-70 years old, or 50-80    years old, or 50-70 years old.-   4.22 Any preceding method, wherein the patient suffers from a    co-morbidity, for example, conjunctivitis, stye, chalazion,    blepharitis, ectropion, eyelid laxity, eyelid edema, eyelid    dermatitis, punctate keratopathy, or ocular allergies, or any    combination thereof.-   4.23 Any preceding method, wherein the patient suffers from    keratoconjunctivitis sicca which is caused by treatment of a    co-morbidity, for example, treatment with any one or more of:    isotretinoin, sedatives, diuretics, tricyclic antidepressants,    antihypertensives, anticholinergics, oral contraceptives,    antihistamine, nasal decongestants, beta-adrenergic antagonists,    phenothiazines, atropine opiates (e.g., morphine), optionally    wherein any such treatment is concurrent or previous, and further    optionally, wherein any such treatment is systemic (e.g., oral or    parenteral).-   4.24 Any preceding method, wherein the patient suffers from    keratoconjunctivitis sicca which is caused by ocular surgical    intervention, for example, corneal surgery, refractive surgery,    LASIK surgery, cataract surgery, optionally wherein any such ocular    surgery is concurrent or previous.-   4.25 Any preceding method, wherein the patient is concomitantly    under treatment with another topical ophthalmic medication, for    example, an antibiotic, antifungal, corticosteroid, another    immunosuppressant, sympathomimetic, anesthetic, antihistamine, or    any combination thereof.-   4.26 Any preceding method, wherein the patient is a contact lens    wearer.-   4.27 Any preceding method, wherein the patient was unresponsive or    insufficiently responsive to previous treatment for    keratoconjunctivitis sicca (dry eye disease).-   4.28 Method 4.27, wherein said previous treatment comprises one or    more of the following treatment methods: topical aqueous    immunosuppressant administration (e.g., topical aqueous    ciclosporin), topical corticosteroid administration, or topical    aqueous artificial tears administration.-   4.29 Any preceding method, wherein the patient has at least one eye    with any one, or combination of criteria (e.g. signs of dry eye    disease) selected from the group consisting of:    -   i. A total lissamine green conjunctival score (sum of temporal        and nasal regions) of ≥2 according to the Oxford scale;    -   ii. a total corneal fluorescein staining (NEI scale) of ≥10        (i.e. sum of inferior, superior, central, nasal and temporal        regions); and    -   iii. an unanesthetized Schirmer's Test score between 1 mm and 10        mm;    -   and/or    -   wherein the patient has a total ocular surface disease index        score (OSDI) of equal or greater than 20.-   4.30 Any preceding method, wherein the patient has a total ocular    surface disease index score (OSDI) of equal or greater than 45.-   4.31 Any preceding method, wherein the patient has a total ocular    surface disease index score (OSDI) of equal or greater than 55.-   4.32 Method 4.29 to 4.31, wherein the patient has at least one eye    (i.e. the same eye) which meets all of criteria (i), (ii), and    (iii).-   4.33 Any preceding method, wherein the patient has a history of    keratoconjunctivitis sicca (dry eye disease) in one or both eyes for    at least six months.-   4.34 Any preceding method, wherein the composition is effective in    reducing one or more signs and/or symptoms of keratoconjunctivitis    sicca (dry eye disease), preferably wherein the signs and/or    symptoms is selected from ocular surface damage-   4.35 Any preceding method, wherein the composition is effective in    reducing one or more signs and/or symptoms of keratoconjunctivitis    sicca (dry eye disease) within 2 weeks, or within 4 weeks, or within    8 weeks after first administration of the composition.-   4.36 Any preceding method, wherein the composition is effective in    reducing ocular surface damage.-   4.37 Method 4.36, wherein the ocular surface damage is selected from    the group consisting of:    -   i. surface damage of the total corneal region;    -   ii. surface damage of the central corneal region;    -   iii. surface damage of the nasal corneal region;    -   iv. surface damage of the temporal corneal region;    -   v. surface damage of the inferior corneal region; and    -   vi. combinations thereof.-   4.38 Method 4.37, wherein the ocular surface damage is selected from    ocular surface damage in the central corneal region and ocular    surface damage of the inferior corneal region.-   4.39 Method 4.36 to 4.38 wherein the reduction of ocular surface    damage is determined by corneal fluorescein staining (NEI scale).-   4.40 Method 4.39, wherein the corneal fluorescein staining method is    selected from the group consisting of:    -   iv. total corneal fluorescein staining;    -   v. central corneal fluorescein staining;    -   vi. nasal corneal fluorescein staining;    -   vii. temporal fluorescein staining;    -   viii. inferior corneal fluorescein staining; and    -   ix. any combination thereof.-   4.41 Any preceding method, wherein the composition is effective in    reducing the frequency of dryness and/or the awareness of dry eye    symptoms and/or the severity of dryness and any combination thereof.-   4.42 Method 4.41, wherein the composition is effective in reducing    the frequency of dryness and/or the awareness of dry eye symptoms    and/or the severity of dryness, or any combination thereof, within 2    weeks after start of treatment, or within 4 weeks after start of    treatment.-   4.43 Method 4.41 or 4.42 wherein the composition is effective in    reducing the frequency of dryness and/or the severity of dryness by    at least 25% after two weeks or after four weeks or after 8 weeks or    after 12 weeks of treatment.-   4.44 Method 4.41 to 3.43, wherein the composition is effective in    reducing the severity of dryness and/or the frequency of dryness by    at least 25% in more than 20% of patients undergoing treatment after    two weeks of treatment; or in more than 30% of patients undergoing    treatment after four weeks of treatment; or in more than 35% of    patients undergoing treatment after eight weeks of treatment.-   4.45 Method 4.41 to 4.44, wherein the effectiveness of the    composition for use is determined by visual analog scale (VAS)    testing on a scale of 0 to 100%, wherein frequency of dryness and    awareness of dry eye symptoms are measured on a scale of 0 to 100%    as the percentage of time said symptom(s) is experienced by a    patient and wherein the severity of dryness is measured on a scale    of 0 to 100% as the percentage level of discomfort experienced by    the patient.-   4.46 Any preceding method, wherein the method of treatment comprises    reducing ocular surface damage, e.g. ocular surface damage of the    cornea, or ocular surface damage selected from i. surface damage of    the total corneal region; ii. surface damage of the central corneal    region; iii. surface damage of the nasal corneal region; iv. surface    damage of the temporal corneal region; v. surface damage of the    inferior corneal region; and vi. combinations thereof.-   4.47 Method 4.46, wherein the ocular surface damage is selected from    ocular surface damage in the central corneal region and ocular    surface damage of the inferior corneal region.-   4.48 Method 4.46 to 4.47 wherein the ocular surface damage is    determined by corneal fluorescein staining (NEI scale).-   4.49 Any preceding method, wherein the patient has at least one eye    with any one or combination of criteria selected from the group    consisting of:    -   a total corneal fluorescein staining value in the range of 10 to        15, preferably 10 to 13 (NEI scale);    -   a central corneal fluorescein staining value in the range of 1        to 3 (NEI scale);    -   preferably 2 to 3 (NEI scale);    -   a total lissamine green conjunctival staining score in the range        of 2 to 6, preferably 3 to 5;    -   an unanesthetized Schirmer's test score in the range of 2 to 8        mm;    -   a total OSDI score in the range of 25 to 64, preferably 30 to        64.-   4.50 Any preceding method, in which the patient does not suffer from    blepharitis and/or meibomian gland dysfunction.-   4.51 Any preceding method, wherein the patient has an unanesthetized    Schirmer's Test score in the range of 3 to 7 mm, preferably in the    range of 4 to 6 mm, more preferably of about 5 mm.-   4.52 Any preceding method, wherein the method is effective in    reducing in a patient the total corneal fluorescein staining score    (sum of inferior, superior, central, nasal, and temporal staining    scores; NEI scale), by at least 3 grades after 4 weeks of treatment,    preferably in at least 50% of the patients undergoing treatment.-   4.53 Any preceding method, wherein the method is effective in    reducing the central corneal fluoresceing staining score in a    patient by at least 1 grade after four weeks of treatment,    preferably in at least 50% of the patients undergoing treatment.-   4.54 Any preceding method, wherein the method is effective in    reducing the conjunctival lissamine green staining (Oxford scale) in    a patient by at least 2 grades after four weeks or after twelve    weeks of treatment, preferably in at least 30% of the patients    undergoing treatment after four weeks of treatment or preferably in    at least 50% of the patients after twelve weeks of treatment.-   4.55 Any preceding method, wherein the patient has at least one eye    with a total corneal fluorescein staining score at least equal or    higher than 11 (NEI scale).-   4.56 Any preceding method, wherein the patient has at least one eye    with a central corneal fluorescein staining value in the range of 1    to 3 (NEI scale).-   4.57 Any preceding method, wherein the patient has at least one eye    with a total lissamine green conjunctival staining score in the    range of 2 to 6.-   4.58 Any preceding method, wherein the patient has at least one eye    with an unanesthetized Schirmer's test score in the range of 4 to 6    mm.-   4.59 Any preceding method, wherein the central corneal fluorescein    staining value is about 3 (NEI scale).-   4.60 Any preceding method, wherein the lissamine green conjunctival    staining score is in the range of 3 to 5.-   4.61 Any preceding method, wherein the unanesthetized Schirmer's    test score is about 5 mm.-   4.62 A method of treating and/or ameliorating the symptoms    associated with keratoconjunctivitis sicca (dry eyes) wherein the    symptoms are dryness (severity of dryness) and blurred vision,    wherein the method comprises administering an ophthalmic composition    comprising 0.1% (w/v) cyclosporine dissolved in    1-(perfluorobutyl)pentane to an eye of a patient, and wherein the    patient has at least one eye with a total corneal fluorescein    staining score at least equal or higher than 11 (NEI scale).-   4.63 Method 4.62 and/or a method of treating and/or ameliorating the    awareness of symptoms of dry eyes and the frequency of dryness,    preferably wherein the symptoms of dry eye are selected from    dryness, sticky feeling, burning/stinging, foreign body sensation,    itching, blurred vision, sensitivity to light, and pain, wherein    said method comprises administering an ophthalmic composition    comprising 0.1% (w/v) cyclosporine dissolved in    1-(perfluorobutyl)pentane to an eye of a patient, and wherein the    patient has at least one eye with a total corneal fluorescein    staining score at least equal or higher than 11 (NEI scale).-   4.64 Method 4.62 or 4.63, wherein the patient has at least one eye    with a central corneal fluorescein staining value in the range of 1    to 3 (NEI scale).-   4.65 Method 4.62 to 4.64, wherein the patient has at least one eye    with a total lissamine green conjunctival staining score in the    range of 2 to 6.-   4.66 Method 4.62 to 4.65, wherein the patient has at least one eye    with an unanesthetized Schirmer's test score in the range of 4 to 6    mm.-   4.67 Method 4.64 to 4.66, wherein the central corneal fluorescein    staining value is about 3 (NEI scale).-   4.68 Method 4.65 to 4.67, wherein the lissamine green conjunctival    staining score is in the range of 3 to 5.-   4.69 Method 4.66 to 4.68, wherein the unanesthetized Schirmer's test    score is about 5 mm.-   4.70 Method 4.62 to 4.69, wherein the patient has a total ocular    surface disease index score (OSDI) of equal or greater than 45.-   4.71 Method 4.62 to 4.70, wherein the patient has a total ocular    surface disease index score (OSDI) of equal or greater than 55.-   4.72 Method 4.55 to 4.71, wherein the patient has the total corneal    flueorescein staining score, the central corneal fluorescein    staining value, the lissamine green conjunctival staining score,    and/or the unanesthetized Schirmer's test score with the specified    values in both eyes.

In another aspect, the present invention provides for the followingmethod:

-   5.1 A method for predicting the improvement of visual function in a    subject suffering from dry eye disease (keratoconjunctivitis sicca)    and characterized by a total corneal fluorescein staining score in    the range of 10 to 15 (NEI scale) at baseline, wherein a decrease of    the total corneal fluorescein staining score (NEI scale) by 3 or    more units is indicative for improvement of visual function.-   5.2 The method according to item 5.1, wherein the improvement of    visual function comprises improvement in the number of words read    per minute in an international reading speed texts (IReST).-   5.3 The method according to item 5.1 or 5.2, wherein the improvement    of visual function comprises improvement with regard to blurred    vision, reading, driving at night, working with a computer, working    at an automatic teller machine, reading at low contrast and reading    at low print size.-   5.4 The method according to any preceding items, wherein the subject    is undergoing treatment that is effective in reducing ocular surface    damage.-   5.5 The method according to item 5.4, wherein the treatment is    selected from a) an ophthalmic composition comprising cyclosporine    at a concentration of from 0.05 to 0.1% (w/v) or b) an ophthalmic    composition comprising lifitegrast.-   5.6 The method according to any preceding items, wherein the    treatment is a composition comprising 0.1% (w/v) cyclosporine    dissolved in 1-perfluorobutyl-pentane and up to about 1% (w/w)    ethanol.-   5.7 The method according to item 5.6, wherein the composition is    administered in a dose of a single drop per eye in volume of about 8    to 12 μL.-   5.8 The method according to item 5.7, wherein the composition is    administered as a single drop per eye having a volume of about 10-12    μl.-   5.9 The method according to any of items 5.6-5.8, wherein the    composition is administered twice per day per eye.-   5.10 Any preceding method, wherein the subject has at least one eye    with a total corneal fluorescein staining score at least equal or    higher than 11 (NEI scale).-   5.11 Any preceding method, wherein the subject has at least one eye    with a central corneal fluorescein staining value in the range of 1    to 3 (NEI scale).-   5.12 Any preceding method, wherein the subject has at least one eye    with a total lissamine green conjunctival staining score in the    range of 2 to 6.-   5.13 Any preceding method, wherein the subject has at least one eye    with an unanesthetized Schirmer's test score in the range of 4 to 6    mm.-   5.14 Any preceding method, wherein the central corneal fluorescein    staining value is about 3 (NEI scale).-   5.15 Any preceding method, wherein the lissamine green conjunctival    staining score is in the range of 3 to 5.-   5.16 Any preceding method, wherein the unanesthetized Schirmer's    test score is about 5 mm.-   5.17 A method for predicting the improvement of visual function in a    subject suffering from dry eye disease (keratoconjunctivitis sicca)    and characterized by a total corneal fluorescein staining score at    least equal or higher than 11 (NEI scale) at baseline, wherein a    decrease of the total corneal fluorescein staining score (NEI scale)    by 3 or more units is indicative for improvement of visual function.-   5.18 Method 5.17, wherein the subject has at least one eye with a    central corneal fluorescein staining value in the range of 1 to 3    (NEI scale).-   5.19 Method 5.17 or 5.18, wherein the subject has at least one eye    with a total lissamine green conjunctival staining score in the    range of 2 to 6.-   5.20 Method 5.17 to 5.19, wherein the subject has at least one eye    with an unanesthetized Schirmer's test score in the range of 4 to 6    mm.-   5.21 Method 5.18 to 5.20, wherein the central corneal fluorescein    staining value is about 3 (NEI scale).-   5.22 Method 5.19 to 5.21, wherein the lissamine green conjunctival    staining score is in the range of 3 to 5.-   5.23 Method 5.20 to 5.22, wherein the unanesthetized Schirmer's test    score is about 5 mm.-   5.24 Method 5.17 to 5.23, wherein the subject has a total ocular    surface disease index score (OSDI) of equal or greater than 45.-   5.25 Method 5.17 to 5.24, wherein the subject has a total ocular    surface disease index score (OSDI) of equal or greater than 55.-   5.26 Method 5.10 to 5.25, wherein the patient has the total corneal    flueorescein staining score, the central corneal fluorescein    staining value, the lissamine green conjunctival staining score,    and/or the unanesthetized Schirmer's test score with the specified    values in both eyes.

In a further aspect, the present invention provides for an ophthalmiccomposition for use in a method of increasing tear production volume ina subject, wherein the composition comprises 0.1% w/v cyclosporinedissolved in 1-(perfluorobutyl)pentane. Said method may comprise a stepof topically administering the composition to an eye of a subject, forexample to the surface of the eye (e.g. the surface of the cornea and/orconjunctiva). The composition may be administered in the form of asingle (i.e. one) liquid drop per dose. Preferably, the drop volume ofsaid administered dose is between about 8 to 10 μL. In one embodiment ofsaid aspect, the composition may be administered twice a day per eye ofthe subject. The composition according to said aspect may comprise ofabout 0.1% w/v cyclosporine dissolved in 1-(perfluorobutyl)pentane, andoptionally, up to about 1.0% w/w of ethanol. In another embodimentaccording to this aspect, the composition for use in said method ofincreasing tear production volume in a subject may be a solutionconsisting of about 0.1% w/v cyclosporine dissolved in1-(perfluorobutyl)pentane and about 1.0% w/w ethanol. In yet a furtherembodiment according to this aspect, the composition is a solutionconsisting of about 0.1% w/v cyclosporin dissolved in1-(perfluorobutyl)pentane.

The ophthalmic composition for use according to this aspect and any oneof its embodiments above may be used in a method of increasing tearproduction volume in a subject, wherein the subject's tear production issuppressed, or presumed to be suppressed because of ocular inflammationassociated with keratoconjunctivitis sicca. Tear suppression, such asdue to ocular inflammation associated with keratoconjunctivitis sicca inthe subject may for example be determined in a subject based on any oneor combination of the methods as described herein used to assay dry eyedisease signs and symptoms, for example Schirmer type I test or cornealfluorescein staining, or patient questionnaire.

In another aspect, the present invention provides for an ophthalmiccomposition for use in a method of treating xerophtalmia, wherein thecomposition comprises 0.1% w/v cyclosporine dissolved in1-(perfluorobutyl)pentane. Preferably said treatment method increasestear production in the subject. The method according to said aspect maycomprise a step of topically administering the composition to an eye ofa subject, for example to the surface of the eye (e.g. the cornea and/orconjunctiva). The composition may be administered in the form of asingle liquid drop per dose; in an embodiment, the volume of theadministered drop is between about 8 to 10 μL. The composition may beadministered twice daily (two times per day) per eye of the subject. Inone embodiment, the composition according to said aspect may comprise ofabout 0.1% w/v cyclosporine dissolved in 1-(perfluorobutyl)pentane, andoptionally, up to about 1.0% w/w of ethanol.

In another embodiment according to this aspect, the composition for usein said method of treating xerophtalmia, optionally wherein the methodincreases tear production in a subject, is a solution consisting ofabout 0.1% w/v cyclosporine dissolved in 1-(perfluorobutyl)pentane andabout 1.0% w/w ethanol. In an alternative embodiment according to thisaspect, the composition is a solution consisting of 0.1% w/v cyclosporindissolved in 1-(perfluorobutyl)pentane.

Damage to the cornea and associated tissues is prevalent in patientswith dry eye disease, in particular those with moderate to severe, orsevere dry eye disease. The tear film, with its lipid, aqueous and mucinlayers normally provides a protective barrier to corneal tissue andcorneal epithelium and has a wetting function i.e. preventsdrying/desiccation. It acts as a conduit for the provision of oxygen andnutrients to the corneal epithelial cells, as well as removal of anypotential pathogens, debris and waste products. In patients with dry eyedisease, the tear film is typically unstable or disrupted (for example,as a result of reduced aqueous secretion or increased evaporation of thetear film, or reduced secretion of mucin or lipids) and consequently,the corneal tissue, and conjunctiva may become less protected andvulnerable and/or prone to damage and deterioration.

The severity of ocular surface damage which may be characterized by, forexample punctate disruption of the corneal epithelium or surfacedisruption of the bulbar conjunctiva, may be assessed by corneal andconjunctival staining measurements, for example such as describedherein, i.e. fluorescein staining (NEI scale) and lissamine greenstaining (Oxford scale), which highlight and stain in particular, deador damaged corneal and conjunctival cells. Particularly, central cornealfluorescein staining (NEI scale), which assays the central corneal area(as compared to the peripheral corneal area including inferior,superior, nasal, and temporal regions of the cornea), reflects ocularsurface damage that impacts visual function impairment.

As used herein, the term ‘corneal staining’ or ‘total corneal staining’,optionally in conjunction with the mention of fluorescein, or a dye thatis suitable or adapted for staining of the cornea, refers to stainingobserved as a sum in respect of all regions of the cornea, i.e. theinferior, superior, central, temporal, and nasal regions of the cornea.The term ‘central corneal staining’ or the like (i.e. with specificcorneal region prefacing) and optionally in conjunction with the dyeused for staining, such as fluorescein, refers specifically to stainingobserved only in the specified anatomical region.

As used herein, the term ‘conjunctival staining’ or ‘total conjunctivalstaining’, optionally in conjunction with the mention of fluorescein ora dye suitable or adapted for staining of the cornea, refers to stainingobserved as a sum in respect of all regions of the conjunctivis, i.e.the temporal and nasal regions of the conjunctivis. Where the term isused specifying the specific conjunctival region (e.g. nasal conjunctivastaining), optionally in conjunction with mention of the dye used forstaining, such as lissamine green, it is to be understood that thisrefers specifically to staining observed in said region.

In one embodiment, the ophthalmic composition for any one of the usesaccording to the invention may be used to treat and reduce the signs ofdry eye diseases, in particular treat or reduce ocular surface damage,such as corneal damage and/or conjunctival damage, in a subjectsuffering from dry eye disease. In one embodiment, said subject to betreated may have ocular surface damage of the cornea, and have a totalcorneal fluorescein staining score of at least equal to, or greater than10 (≥10), the score being the sum of scores obtained for inferior,superior, central, nasal, and temporal regions of the cornea, based onthe NEI grading scale of 0-3. In another embodiment, the subject mayhave a total corneal fluorescein staining score of at least equal to, orgreater than 11, prior to commencement of treatment, optionally whereinthe subject has a total OSDI score of equal to or greater than 45, orequal or greater than 55.

In another embodiment, the ophthalmic composition according to any oneof the uses according to the invention may be used to reduce ocularsurface damage, such as corneal damage and/or conjunctival damage, in asubject suffering from dry eye disease. In one embodiment, said subjectmay have a central corneal fluorescein staining score of at least equalto, or greater than 2 (≥2), based on the NEI grading scale of 0-3. Inanother embodiment, said subject may in addition also have a totallissamine green conjunctival staining score (sum of temporal and nasalregions), based on the Oxford scale, of at least equal to, or greaterthan 2 (i.e. ≥2).

In one embodiment, the invention relates to an ophthalmic compositionfor use in treating i.e. reducing ocular surface damage in a subjectsuffering from dry eye disease, wherein said subject has a total OSDIscore of equal, or greater than 45, wherein the composition comprisesabout 0.1% (w/v) cyclosporine dissolved in 1-(perfluorobutyl)pentane,and optionally up to about 1.0% (w/w) of ethanol; wherein thecomposition is administered topically twice daily, one drop per eye at adrop volume of about 8 to 10 μL. In another specific embodiment, suchuse may be for the treatment e.g. reduction of corneal surface damage,in particular reduction of ocular surface damage of the central cornealregion and/or the inferior corneal region.

In a further embodiment, said ophthalmic composition may be used in theeffective treatment of patients with dry eye disease with signs ofcorneal ocular surface damage (e.g. with total corneal staining scores(NEI scale) of at least 11) wherein the composition is administeredtwice daily. Said composition may be topically administered as a singledrop per dose and per eye, said drop having a volume of about 10 μL.

In another embodiment, the present disclosure relates to an ophthalmiccomposition comprising 0.1% (w/v) cyclosporine dissolved in1-(perfluorobutyl)pentane for use in: a) a method of treating and/orameliorating the symptoms associated with keratoconjunctivitis sicca(dry eye disease), wherein the symptoms are dryness, and blurred vision;and/or b) for use in a method of treating and/or ameliorating theawareness of symptoms of dry eye disease and the frequency of dryness.

Optionally, the method of treatment according to said embodimentcomprises topical administration twice daily of a single drop of thecomposition per eye, further optionally at a drop volume of about 8 to10 μL. In yet a further embodiment, said composition may consist of 0.1%(w/v) cyclosporine dissolved in 1-(perfluorobutyl)pentane and optionallyup to 1.0% (w/w) of ethanol.

As used herein, the term ‘severity of dryness’ may be usedinterchangeably with the term (ocular) ‘dryness’, which refers to thesymptomatic ocular sensation of dryness which may be experienced bypatients with keratoconjunctivitis sicca (dry eye disease).

It has been found that the composition for use as defined above issurprisingly efficacious in treating, i.e. reducing the degree ofseverity in particular in dry eye symptoms selected from dryness andblurred vision. As noted above, dryness refers to the ocular sensationof dryness, and is the first question of the VAS questionnaire asdescribed below. Blurred vision may refer to for example a certaindegree of impaired vision, e.g. objects/text appear to subjects withblurred vision to be less well-defined or unclear, or may appearpartially obscured. These symptoms may contribute to overall visualimpairment or difficulties, which can have a negative effect on thesubject's performance in functional tasks where visual performance andacuity may be essential. Thus a positive and in particular early impactin terms of alleviating and reducing these symptoms in subjects can beparticularly beneficial, in terms of improving quality of vision andproviding relief, and in particular in subjects for which the discomfortlevel of these symptoms is very high and frequent.

As well as a reduction in severity of dryness and blurred vision, thepresent composition according to the invention has also been found to beeffective in reducing the overall degree of frequency of dryness. Areduction in frequency in which dryness, is experienced by a subject,and/or reduction in a subject's overall awareness of dry eye symptoms,may also be beneficial in terms of improving overall quality of visionand would allow the subject undertake activities, which may bepreviously may be severely limited due to frequent irritation ordistraction due to constant awareness or occurrence of dry eye symptoms.

The amelioration of these symptoms may be based on, and determined byapplication of the visual analog scale (VAS) eye dryness test, whereinthe patients are assessed over the course of treatment in respect ofsaid symptoms on a scale of 0-100% level of discomfort, as well as on ascale of 0 to 100%, the percentage of time in which they are aware of,or experience (i.e. frequency) the symptoms in their eyes.

In one embodiment, the compositions for any of the uses of the presentinvention are effective in improving by at least 25% a reduction in theseverity of dryness (e.g. ocular dryness) and/or the frequency ofdryness experienced by a patient or subject as described herein. Inanother embodiment, the composition is effective in providing at least a25% reduction in severity of dryness and frequency of dryness within 2weeks of commencement of the treatment. In another embodiment, thecomposition is effective in providing at least a 25% reduction inseverity of dryness and frequency of dryness within 2 weeks ofcommencement of the treatment in at least 25% of the subjects undergoingthe treatment. In a further embodiment, the treatment is effective inproviding at least 25% reduction in severity of dryness and/or frequencyof dryness, within 4 weeks of commencement i.e. start of the treatmentin at least 30% of the subjects undergoing the treatment. The reductionmay be determined by comparison of VAS scoring for each or combinationof the above symptoms with initial baseline scores obtained prior totreatment.

In further embodiments, the method of treating keratoconjunctivitissicca (dry eye disease) may comprise the topical administration of acomposition according to the invention to an eye, or both eyes of apatient and treating or ameliorating the frequency of dryness and/orawareness of the symptoms associated with dry eye disease (e.g. symptomsselected from dryness, sticky feeling, burning/stinging, foreign bodysensation, itching, blurred vision, sensitivity to light, and pain),wherein said treatment comprises an effective reduction of the frequencyof dryness or awareness of dry eye symptoms in general, of at least 25%,within 2, or within 4 weeks after the start of treatment.

Optionally, the ophthalmic composition and dosage thereof as describedherein may be used for treating patients or subjects who are notresponsive, or who are insufficiently responsive to treatment withaqueous artificial tears.

Artificial tears, also known as lubricating eye drops or tearsubstitutes are used for relief and treatment of the symptoms of dry eyedisease, and which normally may be obtained over the counter (OTC).These are normally aqueous-based compositions, in the form of solutions,but also in the form of gels or ointments which function by addingmoisture to the eyes, and usually may comprise lubricating agents (e.g.hydroxypropyl methyl cellulose (HPMC), carbomethylcellulose (CMC),polyvinyl alcohol, liquid polyols such as propylene glycol, polyethyleneglycol) and may contain additives which promote healing (e.g. hyaluronicacid) or mimic electrolyte composition of natural tear film, or whichpromote retention (e.g. gelling agents such as carbomers) of thecomposition on the eye surface.

In an embodiment, the ophthalmic compositions for any one of the usesaccording to the invention may be used to treat patients with persistingdry eye disease symptoms and associated conditions even following atreatment period with only aqueous artificial tears over a period of atleast 2 weeks, or at least 1 month, or at least about 6 months.

A dose of a composition for any one of the uses according to the presentinvention and as described in any one of the embodiments herein istopically administered in the form of a (i.e. one) single drop to an eyeof a subject. The drop may be administered to the surface of the eye,preferably to any surface region or tissue of the eye that is accessibleto topical administration or instillation, for example to the cornea orconjunctiva. The single drop of the composition may be instilleddirectly onto a surface of the eye, such as the corneal surface of theeye, or alternatively into a space i.e. sac or pocket formed by gentlypulling down of the lower eyelid of an eye.

As used herein, the term ‘administration to an eye’ or ‘per eye’ refersto the administration of a given dose, e.g. a single dose, of aophthalmic composition according to the invention to an individual eyeof a subject. The therapy of the dry eye disease and dry eye diseaseassociated conditions as described herein however, should be understoodas being not limited to the treatment of a single eye in a subject, butas being also inclusive of a therapy involving the administration ofcompositions according to the present invention to each i.e. both eyesof a subject which are affected by the dry eye condition.

In an embodiment of the invention, the ophthalmic compositions for anyof the uses described herein are administered at a dose of a single droptwo times a day per eye. Thus, a patient undergoing treatment for botheyes in accordance with such dosing scheme would receive a total of twodrops for each eye on each day of a given treatment period.

Where the ophthalmic composition is administered more than once per dayto each eye, for example two times daily per eye, in a furtherembodiment, the time interval between topical administration of thecomposition to the eye or eye surface of the first dose and the seconddose may be at least 4 hours, or at least 6 hours, or at least 12 hours.

In a further embodiment, the ophthalmic compositions for any of the usesof the present invention are administered over a treatment period of atleast 1 month (four weeks), and more at least 3 months (12 weeks). Inanother embodiment, the ophthalmic compositions for any of the uses ofthe present invention may be administered on a continuous basis whiledry eye disease symptoms and indicators persist.

In other embodiments, the ophthalmic compositions for any of the uses inaccordance with the invention may comprise up to about 1.0% (w/w) ofethanol.

As used herein, the term “up to about” or “up to” used in context of aparameter, such as presently in relation to the amount of ethanol in thecomposition, refers to any value of the parameter greater than zero andup to, and inclusive of, the defined parameter. For example, an amountof “up to about 1.0% (w/w) of ethanol” should be understood as includingany value greater than zero ranging up to and including the value of1.0% (w/w) of ethanol, and would include, for example, values such as0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5% 0.6%, 0.7, 0.8, 0.9, 0.95%,0.99% (w/w) of ethanol, taking into account any degree of variabilityusually observed in measuring or determining this parameter, using thestandard techniques and equipment known in the relevant field.

In one embodiment of the invention, the compositions for the therapeuticuses as described herein may consist essentially of about 0.1% (w/v)cyclosporine dissolved in 1-(perfluorobutyl)pentane, and optionallyabout 1.0% (w/w) of ethanol.

In another embodiment, the compositions as described herein areessentially free of ethanol, in which the composition consistsessentially only of cyclosporine in an amount as described in any of theembodiments described herein dissolved in 1-(perfluorobutyl)pentane.

The absence of an organic co-solvent such as ethanol may offer theadvantages of a simpler two component formulation compared to a threecomponent formulation additionally comprising a co-solvent such asethanol. The further inclusion, of even one additional compositioncomponent may add complexity in terms of factors such as cost,manufacturing, handling, packaging, and also patient compliance.

In preferred embodiments of the invention, the compositions for any ofthe uses as described herein may preferably comprise, or consist of:

about 0.1% (w/v) of cyclosporine dissolved in 1-(perfluorobutyl)pentaneand about 0.5% (w/w) ethanol, orabout 0.1% (w/v) cyclosporine dissolved in 1-(perfluorobutyl)pentane andabout 1.0% (w/w) ethanol, orabout 0.1% (w/v) cyclosporine dissolved in 1-(perfluorobutyl)pentane.

The compositions for any of the uses of the invention are preferablyprovided as a clear solution, wherein the cyclosporine is fullydissolved and in solution in the 1-(perfluorobutyl)pentane (at roomtemperature conditions i.e. between 15 to 25° C.). If ethanol isincluded, said compositions are also provided as a clear solution ofcyclosporine dissolved and in solution in 1-(perfluorobutyl)pentane andthe ethanol. In one embodiment, the compositions are provided in sterileform.

In another embodiment, the ophthalmic compositions for any one of theuses according to the present invention are substantially free of waterand/or substantially free of a preservative. As understood herein, theterm ‘substantially free’, or alternatively ‘essentially free’ inreference to a composition constituent refers to the presence of saidconstituent in no more than trace amounts and that if present in traceamounts the constituent provides no technical contribution to thecomposition.

Preferably, the ophthalmic compositions for any one of the usesaccording to the present invention are substantially free of water,substantially free of a preservative and are effective in inhibitingmicrobial growth.

In another embodiment, the ophthalmic compositions for any one of theuses according to the present invention are characterized by aremarkable wetting and spreading behaviour by which they can rapidly andeffectively spread over the surface of the eye, such as the cornealand/or the conjunctival surface. Thus, a droplet (drop) of theophthalmic compositions for any one of the uses according to the presentinvention when administered to the surface of the eye leads to rapidspreading of the compositions over the corneal and/or the conjunctivalsurface.

Preferably, the ophthalmic compositions for any one of the usesaccording to the present invention form small droplets (drops), in therange of about 8-10 μl, such as about 10 μL when administered from adrop dispenser.

In another preferred embodiment, the ophthalmic compositions for any oneof the uses according to the present invention are characterized by thecomparable low amount of cyclosporine administered in a single dose pereye, such as about 10 μg cyclosporine administered in a single dose pereye, or about 8 to 10 μg of cyclosporin administered in a single doseper eye.

As used herein, the term “consists” and related terms “consisting” or“consist” is to be understood as meaning that no other features, otherthan those prefaced by the term are present. In the context of theophthalmic compositions as described herein, if any other constituent orcomponent is present in the composition other than those prefaced bysuch term, then it is present only in trace or residual amounts such asto confer no technical advantage or relevance in respect of the objectof the invention, such as may be further understood by the term‘essentially” or “substantially” used in conjunction with these terms(e.g. ‘essentially consisting of”).

The use of an ophthalmic composition as described in any one of theabove embodiments in the manufacture or preparation of a medicament or amedicine for the treatment of a subject in need thereof in relation toany one of preferred dry eye disease conditions described herein arealso provided for in the context of the present invention. Furtherprovided for within the context of the present invention, are alsomethods of treating subjects diagnosed with, and/or suffering from saiddry eye disease conditions as described herein, wherein the methods maycomprise the topical administration, such as by direct topicalinstillation to the eye, of any one of the defined compositions,preferably in any one of the described doses or amounts, and/or over anyone of the defined periods for therapy.

Said treatment methods and compositions for therapeutic use are moreoverpreferably targeted towards human subjects or patients diagnosed and/orsuffering dry eye disease.

In yet a further aspect, the invention provides also a kit comprising anophthalmic composition for any one of the uses according to theinvention and any of the embodiments described above. In an embodiment,the kit comprises a container for holding the ophthalmic composition anda drop dispenser adapted for administering about 8 to 10 μL, or about 10μl volume of the composition per drop. The kit may also further compriseinstructions for use, for examples in the form of a leaflet, packagingor other readable means, indicating use in accordance with any one ofthe uses or methods described herein.

As understood herein, the drop dispenser may be a dispenser orapplicator means which may be mounted, fixed or connected to thecontainer for holding the ophthalmic composition. Preferably, the dropdispenser is adapted for dispensing a single dose in the form of asingle drop of the composition. More preferably, the drop dispenser isadapted for dispensing a single dose of about 8- to 10-μl volume, or isadapted for dispensing a single dose of about 10-μl volume.

The container for holding the ophthalmic composition as understoodherein is preferably of a volume which may hold a single dose, but morepreferably of a volume which may hold multiple or a plurality of dosesof the composition.

The following examples serve to illustrate the invention, however shouldnot to be understood as restricting the scope of the invention.

EXAMPLES Example 1 Study Setup

A Phase 2b/3, multi-center, randomized, double-masked(vehicle)-controlled clinical study to assess the efficacy, and safetyand of topical CyclASol® for treatment of the signs and symptoms of dryeye disease. The study is listed in clinicaltrials.gov under the numberNCT03292809.

Subjects eligible to be randomized received one of the followingtreatments to dose with bilaterally BID for approximately 85 days (fromVisit 1 to Visit 5):

1) CyclASol 0.1% Ophthalmic Solution (Cyclosporine A 0.1% solution)

2) Vehicle Ophthalmic Solution (F4H5)

CyclASol 0.1% Ophthalmic Solution is a clear ophthalmic solution ofCyclosporine A dissolved in 1-(perfluorobutyl)pentane.1-(perfluorobutyl)pentane, which is commonly abbreviated F4H5 is used asthe vehicle. The only other component in the formulation is ethanol 1.0%(w/w) as co-solvent. The administered dose of CyclASol, i.e. a singledrop has a volume of about 8-10 μL.

A 14-day study-run-in period was used for subject selection beforerandomization. During this period, all subjects received Systane®Balance to dose with bilaterally BID.

The study involved 6 visits over the course of approximately 14 weeks:

Visit 0, −Day −14±2 days, Screening;

Visit 1, Day 1, Baseline/Randomization;

Visit 2, Day 15±1 days, 2-Week Follow-Up;Visit 3, Day 29±2 days, 4-Week Follow-Up;Visit 4, Day 57±2 days, 8-Week Follow-Up; andVisit 5, Day 85±2 days, 12-Week Follow-Up and Study Exit.

Study Population

Patients included in the study had to fulfill following criteria:

-   -   (a) Be at least 18 years of age;    -   (b) Provide written informed consent;    -   (c) Have a subject reported history of Dry Eye Disease in both        eyes for at least 180 days before Visit 0;    -   (d) Be currently using (within 30 days before Visit 0)        over-the-counter (OTC) eye drops and/or artificial tears for dry        eye symptoms at Visit 0;    -   (e) Have a total OSDI® score of ≥20 at Visit 0 and Visit 1;    -   (f) Have a total corneal fluorescein staining score of ≥10 (i.e.        sum of inferior, superior, central, nasal, and temporal regions)        according to the NEI scale at Visit 0 and Visit 1;    -   (g) Have a total lissamine green conjunctival score (sum of        temporal and nasal regions) of ≥2 according to the Oxford scale        at Visit 0 and Visit 1;    -   (h) Have an unanesthetized Schirmer's Test score between 1 mm        and 10 mm inclusive at Visit 0 and Visit 1;    -   (i) Have at least one eye, the same eye, satisfy inclusion        criteria f, g, and h; and    -   (j) Be able and willing to follow instructions and participate        in all study assessments and visits.

Each subject must not:

-   -   a. Have any clinically significant slit-lamp findings at Visit 0        that require prescriptive medical treatment and/or in the        opinion of the investigator may interfere with study parameters        including trauma, Steven Johnson Syndrome, advanced epithelial        basement membrane disease;    -   b. Have active blepharitis, meibomian gland dysfunction (MGD) or        lid margin inflammation that required any topical or systemic        antibiotics or topical steroids or other prescription medical        treatment or treatment with hypochlorous acid wipes within last        30 days prior to Visit 0 or will require such treatment during        the study. Any other therapy such as lid scrubs, lid wipes, warm        compresses have to be stable within the last 30 days prior to        Visit 0 and the subject should be willing to continue those        therapies through the study;    -   c. Have abnormal lid anatomy (e.g. incomplete eyelid closure,        entropion, or ectropion) or abnormal blinking;    -   d. Have Dry Eye Disease secondary to scarring from, for example,        irradiation, alkali burns, cicatricial pemphigoid, or        conjunctival goblet cell destruction (i.e. conjunctival goblet        cell destruction because of vitamin A deficiency);    -   e. Have an ocular or periocular malignancy;    -   f. Have any corneal epithelial defect, or have in more than 2 of        the 5 corneal regions >50% confluent corneal staining;    -   g. Have a history of herpetic keratitis;    -   h. Have active ocular allergies or ocular allergies that may        become active during the study period;    -   i. Be diagnosed with an ongoing ocular or systemic infection        (bacterial, viral, or fungal), including a fever, or be        undergoing treatment with antibiotics at Visit 0 or Visit 1;    -   j. Have worn contact lenses within 90 days before Visit 0 or        anticipate using contact lenses during the study;    -   k. Have used any eye drops, gels or scrubs within 2 hours before        Visit 0 or Visit 1;    -   l. Have used topical Cyclosporine A (CsA) or Lifitegrast within        60 days before Visit 0;    -   m. Have participated in a previous CyclASol study (patients who        were assigned to the Restasis treatment arm may enter the        study);    -   n. Have had intraocular surgery or ocular laser surgery within        180 days before Visit 0, or have any planned ocular or eyelid        surgeries during the study period;    -   o. Be a woman who is pregnant, nursing, or planning a pregnancy;    -   p. Be unwilling to submit a urine pregnancy test at Visit 0 and        Visit 5 (or early termination visit) if of childbearing        potential. Non-childbearing potential is defined as a woman who        is permanently sterilized (i.e. has had a hysterectomy,        bilateral tubal ligation, or bilateral oophorectomy), or is        post-menopausal (i.e. without menses for 12 consecutive months);    -   q. Be a woman of childbearing potential who is not using an        acceptable means of contraception. Acceptable methods of        contraception include hormonal contraceptives (i.e. oral,        implantable, injectable, or transdermal contraceptives),        mechanical contraceptives (i.e. spermicide in conjunction with a        barrier such as a diaphragm or a condom), intrauterine devices        (IUD), or the surgical sterilization of the partner. For        non-sexually active females, abstinence may be regarded as an        adequate method of birth control; however, if the subject        becomes sexually active during the study, she must agree to use        adequate birth control as defined above for the remainder of the        study;    -   r. Have an uncontrolled systemic disease;    -   s. Have a known allergy or sensitivity to the study drug or its        components: Cyclosporine A (CsA) or semifluorinated alkanes        (SFA);    -   t. Have active ocular or periocular rosacea or a pterygium;    -   u. Be currently enrolled in an investigational drug or device        study or have used an investigational drug or device within 60        days before Visit 0;    -   v. Have used any topical antiglaucoma medications within 90 days        before Visit 0;    -   w. Have used any topical ocular or facial steroids, or serum        tears, or oral doxycycline, or oral tetracycline within 30 days        before Visit 0;    -   x. Have used systemic steroids (including dermatological        steroids with high potency or large treatment areas) or        immunomodulating agents on a non-stable regimen within 90 days        before Visit 0 or anticipate their use on a non-stable regimen        during the study period;    -   y. Have used any oral medications known to cause ocular drying        (e.g. antihistamines or antidepressants) on a non-stable regimen        within 30 days before Visit 0 or anticipate non-stable use of        oral ocular-drying medication during the study;    -   z. Have a corrected visual acuity greater than or equal to log        MAR+0.7 as assessed by the Early Treatment of Diabetic        Retinopathy Study (ETDRS) scale in either eye at Visit 0 or        Visit 1;    -   aa. Have a condition or be in a situation (e.g. language        barrier) which the investigator feels may put the subject at        significant risk, may confound the study results, or may        interfere with the subject's participation in the study        significantly; or    -   bb. Have received or removed a punctal plug within 90 days        before Visit 0 or anticipate the implant or removal of a punctal        plug during the study.

The full analysis set of patients were, respectively, 162 for CyclAsol0.1% treatment and 166 for vehicle treatment.

At baseline, the CyclAsol 01.% group of patients had the followingcharacteristic: a mean total corneal fluorescein staining NEI scale (SD)of 11.5 (1.26); a mean central corneal fluorescein staining NEI scale(SD) of 2 (0.51); a mean conjunctival staining of 4.1 (1.70); a meantotal OSDI (SD) of 46.9 (16.73); a VAS severity of dryness (SD) of 68.5(21.6); a mean Schirmer test score of 5.2 (2.83).

At baseline, the vehicle group of patients had the followingcharacteristics: a mean total corneal fluorescein staining NEI scale(SD) of 11.5 (1.25); a mean central corneal fluorescein staining NEIscale (SD) of 2 (0.52); a mean conjunctival staining of 4.3 (1.66); amean total OSDI (SD) of 47.1 (16.41); a VAS severity of dryness (SD) of69.9 (20.5); a mean Schirmer test score of 5.1 (2.64).

Instructions for Use

Subjects were instructed to instill one drop of treatment 1) or 2) ineach lower eyelid two times daily (in the morning and in the eveningbefore bed).

Evaluation Criteria

At each visit during the treatment period, each subject was assessed interms of treatment efficacy using tests including: corneal fluoresceinstaining (NEI Grading); conjunctival staining (Lissamine, Oxfordgrading), as well as subject symptom assessment questionnaires such asOcular Surface Disease Index questionnaire (OSDI, ref. Schiffman R. M.et al 2000; 118:615-621.) and visual analogue scale (VAS).

The following efficacy measures were obtained during the study:

Primary Efficacy Measures

The following primary endpoints were tested in order using hierarchicalfixed sequence testing:

-   -   1. Change from baseline in total Corneal fluorescein staining        (NEI scale) at Day 29.    -   2. Change from baseline in Ocular Surface Disease Index (OSDI)        at Day 29.        Key Secondary Efficacy Measures included:    -   Total Corneal fluorescein staining (NEI scale) and change from        baseline to each measured post-baseline visit (other than Day        29)    -   Ocular Surface Disease Index (OSDI) and change from baseline to        each measured post-baseline visit (other than Day 29)    -   Lead/Worst symptom assessment    -   Reading impairment score and change from baseline to each        measured post-baseline visit    -   Unanesthetized Schirmer's Test and change from baseline to each        measured post-baseline visit    -   Central and inferior corneal staining (NEI scale) and changes        from baseline to each measured post-baseline visit

Secondary Efficacy Measures:

-   -   Reading assessment and change from baseline to each measured        post-baseline visit    -   Corneal fluorescein staining other sub-regions (NEI scale) and        changes from baseline to each measured post-baseline visit    -   Ocular Surface Disease Index (OSDI) subtotal scores and changes        from baseline to each measured post-baseline visit    -   Conjunctival lissamine green staining by region and total        (Oxford scale) and changes from baseline to each measured        post-baseline visit    -   Tear film break-up time (TFBUT) and change from baseline to each        measured post-baseline visit    -   Visual analog scale (VAS) and changes from baseline for severity        of: dryness, burning/stinging, sticky feeling, foreign body        sensation, itching, blurred vision, sensitivity to light, pain        and for awareness of dry eye symptoms and frequency of dryness        to each measured post-baseline visit    -   InflammaDry® test (MMP-9) and change from baseline to each        measured post-baseline visit    -   Symptoms as recorded in subject diary to each measured        post-baseline visit

Corneal Staining

For corneal staining (Sook Chun Y et al., Am J Ophthalmol. 2014 May;157(5):1097-102), 5 μl of 2% preservative-free sodium fluoresceinsolution was instilled into the inferior conjunctival cul-de-sac of eacheye. In order to achieve maximum fluorescence, the fluorescein stainingis evaluated only after approximately 3-5 minutes after instillation. AWratten #12 yellow filter was used to enhance the ability to gradefluorescein staining.

The staining was graded with the NEI Grading Scale (The National EyeInstitute grading system), with only the cornea being graded. Cornealfluorescein staining scores were obtained for each of the inferior,superior, central, temporal, and nasal regions of the cornea based on a0-3 scale, where a score of 0 means no staining is observed. The term“total corneal fluorescein staining total score” refers to a sum ofscores from the inferior, superior, central, temporal, and nasal regionsof the cornea.

Conjunctival Lissamine Green Staining

Conjunctival Lissamine Green Staining (Bron A. J. et al, Cornea. 2003;22:640-650) was conducted by instillation of 10 μl of lissamine greensolution into the inferior conjunctival cul-de-sac of a subject. Afterwaiting for approximately 30 seconds the staining was evaluated. Thesubject was instructed to blink several times to distribute thelissamine green. The staining was graded with the Oxford Grading Scale.Herein, the lissamine staining is represented by punctate dots on aseries of panels (A-E). Staining ranges from 0-5 for each panel and 0-10for the total exposed inter-palpebral conjunctiva. Both nasal andtemporal regions were graded separately. A score of 0 means no staining.Total conjunctival lissamine green staining scores were obtained,referring to the sum of scores from both temporal and nasal regions ofthe conjunctiva.

Ocular Surface Disease Index (OSDI)

Ocular Surface Disease Index (OSDI) (ref. Schiffman R M, et al., ArchOphthalmol. 2000; 118:615-621) is a survey tool used for the assessmentof symptoms of ocular irritation in dry eye disease and how they affectfunctioning related to vision. It is a 12-item questionnaire assessingdry eye symptoms and effects on vision-related function in the past weekof a patient's life. The questionnaire has 3 subscales: ocular symptoms,vision-related function, and environmental triggers. Patients rate theirresponses on a 0 to 4 scale with 0 corresponding to “none of the time”and 4 corresponding to “all of the time.” A final score is calculatedwhich ranges from 0 to 100.

The questions assess dry eye symptoms experienced by the patient withinpast week including the following: sensitivity to light, grittysensation, pain or sore eyes, blurriness, and poor vision;vision-related function, in terms of problems in: reading, driving atnight, working on a computer or bank machine, watching television; andin terms of environmental factors or triggers i.e. discomfort during:windy conditions, places with low humidity, and areas with aircondition. Subtotals are obtained for all the questions, as well as thetotal number of questions answered. The OSDI index is assessed based ona scale of 0 to 100, with higher scores representing a greaterdisability. The OSDI index is calculated from the sum of the scoresmultiplied by a factor of 25, over the total number of questionsanswered.

Visual Analog Scale (VAS)

Subjects were asked to rate their ocular symptoms (both eyessimultaneously) due to ocular dryness in a 10-item questionnaire andasked to place a vertical mark on the horizontal line starting at thevalue of 0%, corresponding to no discomfort, and ending at a value of100%, corresponding to maximal discomfort, to indicate the level ofdiscomfort. Subjects were asked about the each of following: dryness(corresponding to the first question in the VAS questionnaire, and alsoreferred to in the text and in the graphs as severity of dryness),sticky feeling (question 2), burning/stinging (question 3), foreign bodysensation (question 4), itching (question 5), blurred vision (question6), sensitivity to light (question 7), and pain (question 8). Subjectswere also asked about their awareness of their dry eye symptoms(question 9) and frequency of dryness (question 10), in terms of thepercentage of time. For these two questions, the value of 0% correspondsto ‘never’ and a value of 100% corresponds to “all of the time”. Theassessment line length of the scale is 100 mm (10 cm), with gradingprovided at every 10 mm (suggesting 10%, 20%, etc).

A comparison may be made between the values indicated by the patient ateach visit, compared to baseline values at Day 1 visit 1, to determinethe effectiveness of treatment.

Schirmer's Test I (without Anesthesia)

Schirmer Tear Test I is performed according to the following procedure.Do not blot prior to the test. Using a sterile Tear Flo Schirmer teststrip, a bend in the strip is made in line with the notch in the strip.The subject is instructed to gaze up and in. The Schirmer test strip isplaced in the lower temporal lid margin of each eye such that the stripfits tightly. Subjects were instructed to close their eyes. After 5minutes have elapsed, the Schirmer strip was removed. The length of themoistened area was recorded (mm) for each eye.

Tear Film Break-up Time (TFBUT)

The examiner instilled 5 μL of 2% preservative-free sodium fluoresceinsolution into the inferior conjunctival cul-de-sac of each eye. Tothoroughly mix the fluorescein with the tear film, the subject wasinstructed to blink several times. In order to achieve maximumfluorescence, the examiner should wait approximately 30 seconds afterinstillation before evaluating TFBUT.

With the aid of a slit-lamp, the examiner monitored the integrity of thetear film, noting the time it takes to form micelles from the time thatthe eye is opened. TFBUT was measured in seconds using a stopwatch and adigital image recording system for the right eye followed by the lefteye. A Wratten #12 yellow filter was used to enhance the ability tograde TFBUT.

For each eye, two measurements were taken and averaged unless the twomeasurements are >2 seconds apart and are each <10 seconds, in whichcase, a third measurement would be taken and the two closest of thethree would be averaged. All values were recorded in the sourcedocument.

Study Results

It was observed that treatment with CyclAsol in dry eye diseasepatients, having at baseline a total OSDI score of equal, or greaterthan 45 (≥45) obtained at the first visit (baseline score) wasparticularly effective (FIG. 1). It was observed that there was asignificant change from the baseline of the total OSDI during thetreatment. In particular, and compared with the vehicle, CyclAsol alsohas a remarkable effect in the group of patients having a total OSDI ≥55at baseline (FIG. 2).

It is also observed, compared to the general population of patients inthe study, the mean change from baseline of total OSDI over the 12-weekcourse of treatment with Cyclasol was generally more significant forpatients having an OSDI ≥45 or ≥55.

It was also found that compared to the vehicle, that the overallawareness and frequency of the symptoms of dry eye disease, assessedusing the dry eye symptom visual analog scale (VAS) test, wassignificantly reduced, compared to baseline visit scoring, already afteronly 4 weeks duration of treatment with CyclASol (FIG. 3).

For the severity of dryness, which corresponds to the question relatingto the symptom of “dryness” in the VAS questionnaire, it was alsoobserved that the mean change from baseline was significant, at already4 weeks of treatment in terms of a reduction in the level of severity ofdryness. The baseline values for VAS severity of dryness were 68.5 and69.9 for CyclAsol 0.1% and vehicle, respectively.

Similarly, a reduction in the severity of blurred vision, which isassessed as part of the VAS (visual analog scale) test was alsoobserved. At primary endpoint visit a statistically significant(p=0.02-0.03) symptoms improvement was shown for the symptoms shown inFIG. 3.

It was also found, that the proportion of patients in the study havingat least 25% or higher improvement (compared to baseline visit values),in terms of a reduction in the severity of dryness as determined by theVAS test was higher for CyclASol at all visits compared to the vehicle.The proportion of patients with a response rate of 25% or higher fromtreatment with CyclASol, with respect to a reduction in severity ofdryness, was about 26%, already at week 2 of the treatment. At 4 weeks,at 8 weeks and at 12 weeks, the percentage of patients with a responserate of 25% or higher, that is with an improvement of 25% or more, forthe reduction in severity of dryness was observed to be 33% 37% and 39%,respectively. Similarly, it was observed that the responder rate for thereduction in the frequency of dryness experienced by the patients, interms of patients having 25% or higher degree of improvement (comparedto baseline visit values), as determined by the VAS testing, was alsohigher for the CyclASol treatment compared to the vehicle. Theproportion of patients with a response rate of 25% or higher fromtreatment with CyclASol, with respect to a reduction in the frequency ofdryness, was 24%, already at week 2 of the treatment. At 4 weeks, at 8weeks and at 12 weeks, the percentage of patients with a response rateof 25% or higher for the reduction in frequency of dryness was observedto be 34%, 42% and 37%, respectively.

The primary endpoint of the study at 4 weeks was met with highstatistical and clinical significance, as shown in FIGS. 5 and 6. Theonset of effect on the total corneal fluorescein staining was as earlyas two weeks and was sustained during the entire study duration (FIG.5). The mean baseline value for tCFS for CyclAsol 0.1% and vehicle was11.5 for both groups. As shown in FIG. 6, more than 50% of all patientsresponded to CyclAsol 0.1% with an improvement of ≥3 grades in totalcorneal fluorescein staining after 4 weeks of treatment.

The region of the cornea which benefited most of the CyclAsol 0.1%treatment was the central area, which is the most important region forvisual function. As shown in FIG. 7, an improvement in central cornealfluorescein staining ≥1 grade was obtained in 58.6% of the subjectsundergoing CyclAsol 0.1% treatment after 4 weeks treatment.

A high responder rate was obtained also on conjunctiva. In FIG. 8 it isshown that after 12 weeks treatment, 50.3% of the patients undergoingCyclAsol 0.1% treatment improved of at least 2 grades in conjunctivallissamine green staining score, which is a sign relevant for ocularhealth. FIG. 9 shows the change from baseline of the conjunctivallissamine green staining in the two patients populations. The baselinevalues for the CyclAsol 0.1% group and vehicle group are respectively4.1 and 4.3.

1-16. (canceled)
 17. A kit comprising: (a) a container for holding anophthalmic composition; (b) a drop dispenser adapted for dispensing asingle drop of the composition of about 8 to 10 μl volume, wherein thedrop dispenser is mounted, fixed or connected to the container forholding the ophthalmic composition; and (c) instructions for use of theophthalmic composition in a method of treating keratoconjunctivitissicca (dry eye disease); wherein the ophthalmic composition comprises0.1% (w/v) cyclosporine dissolved in 1-(perfluorobutyl)pentane and up toabout 1.0% (w/w) ethanol; and wherein the method recited in theinstructions comprises the step of topically administering a dose of asingle drop of the composition twice daily to an eye of a patient,wherein said patient has at least one eye with a total ocular surfacedisease index score (OSDI) of equal or greater than 55; and wherein saidpatient has at least one eye with: (i) a total corneal fluoresceinstaining of at least 11 (NEI scale); or (ii) a central cornealfluorescein staining score of 2 to 3 (NEI scale); or (iii) a totallissamine green conjunctival staining score in the range of 2 to 6; or(iv) an unanesthetized Schirmer's test score in the range of 2 to 8 mm;or (v) any combination of (i) to (iv); or (vi) any combination of (i) to(iv), with the specified values in both eyes.
 18. The kit according toclaim 17, wherein the container holds multiple, or a plurality of dosesof the composition.
 19. A method for improving the visual function, orpredicting the improvement of visual function, of a patient sufferingfrom dry eye disease (keratoconjunctivitis sicca), wherein the patientis characterized by having at least one eye with a total cornealfluorescein staining score of at least 11 (NEI scale) at baseline,wherein the improvement in visual function in the patient ischaracterized by a reduction in the total corneal fluorescein stainingscore (NEI scale) by three or more units, and wherein the methodcomprises the step of administering to the eye of the patient acomposition comprising 0.1% (w/v) cyclosporine dissolved in1-(perfluorobutyl)-pentane and up to about 1% (w/w) ethanol; whereinsaid composition is administered twice per day per eye, at a dose of asingle drop per eye of a volume of about 8 to 12 μL.
 20. The method ofclaim 19, wherein the method comprises administering the composition fora period of at least four weeks.
 21. The method of claim 19, wherein theimprovement of visual function is further characterized by animprovement in the number of words read per minute in an internationalreading speed texts (IReST).
 22. The method of claim 19, wherein theimprovement of visual function is further characterized by animprovement of any one or a combination of blurred vision, reading,driving at night, working with a computer, working at an automaticteller machine, reading at low contrast, and reading at low print size.23. The method of claim 19, wherein the composition is administeredtwice per day per eye, at a dose of a single drop per eye of a volume ofabout 8 to 10 μL.
 24. The method of claim 19, wherein the patient has atleast one eye with a total ocular surface disease index score (OSDI) ofequal or greater than 55, and at least one eye with: (i) a total cornealfluorescein staining score at least 11 (NEI scale); or (ii) a centralcorneal fluorescein staining value of about 1 to 3 (NEI scale); or (iii)a total lissamine green conjunctival staining score in the range of 2 to6; or (iv) an unanesthetized Schirmer's test score in the range of 4 to6 mm; or (v) any combination of (i) to (iv); or (vi) any combination of(i) to (iv), with the specified values in both eyes.
 25. The methodaccording to claim 24, wherein the central corneal fluorescein stainingvalue is about 3 (NEI scale).
 26. The method according to claim 24,wherein the lissamine green conjunctival staining score is in the rangeof 3 to
 5. 27. The method according to claim 19, wherein a decrease ofthe total corneal fluorescein staining score (NEI scale) by 3 or moreunits is indicative for improvement of visual function.
 28. A method oftreating and/or ameliorating the symptoms of dryness associated withkeratoconjunctivitis sicca (dry eye disease) in a patient in needthereof, wherein the method comprises topically administering anophthalmic composition comprising 0.1% (w/v) cyclosporine dissolved in1-(perfluorobutyl)pentane, and up to about 1.0% (w/w) ethanol, whereinthe composition is administered in a dose of a single drop per eye in avolume of about 8 to 10 μL, twice per day per eye; wherein thecomposition is effective in reducing the frequency of the symptom ofdryness and/or the severity of dryness within 4 weeks after start oftreatment; and wherein the patient has at least one eye with a totalocular surface disease index score (OSDI) of equal or greater than 55;and wherein the patient has at least one eye with: (i) a total cornealfluorescein staining score of at least 11 (NEI scale); or (ii) a centralcorneal fluorescein staining value of about 2 to 3 (NEI scale); or (iii)a lissamine green conjunctival staining score in the range of 2 to 6; or(iv) an unanesthetized Schirmer's test score in the range of 2 to 8 mm;or (v) any combination of (i) to (iv); or (vi) any combination of (i) to(iv), with the specified values in both eyes.
 29. The method of claim28, wherein the effectiveness in reduction in the frequency of drynessor the severity of dryness, or combination thereof is determined byvisual analog scale (VAS) testing on a scale of 0 to 100%, whereinfrequency of dryness and awareness of dry eye symptoms are measured on ascale of 0 to 100% as the percentage of time said symptom(s) isexperienced by a patient and wherein the severity of dryness is measuredon a scale of 0 to 100% as the percentage level of discomfortexperienced by the patient.
 30. The method of claim 28, wherein thecomposition is effective in reducing the frequency of dryness and/or theseverity of dryness by at least 25%, preferably by at least 30% afterfour weeks, as determined by visual analog scale (VAS) testing on ascale of 0 to 100%, wherein frequency of dryness and awareness of dryeye symptoms are measured on a scale of 0 to 100% as the percentage oftime said symptom(s) is experienced by a patient and wherein theseverity of dryness is measured on a scale of 0 to 100% as thepercentage level of discomfort experienced by the patient.
 31. Themethod of claim 28, wherein the method is effective in reducing in apatient the total corneal fluorescein staining score in at least one eye(sum of inferior, superior, central, nasal, and temporal stainingscores; NEI scale), by at least 3 grades after 4 weeks of treatment,preferably in at least 50% of the patients undergoing treatment.
 32. Themethod of claim 28, wherein the dry eye disease is aqueous-deficient dryeye disease.
 33. The method of claim 28, wherein the dry eye disease isevaporative dry eye disease.
 34. The method of claim 28, wherein thepatient is non-responsive, or insufficiently responsive, to treatmentwith aqueous ophthalmic eye drop compositions.
 35. A method of treatingkeratoconjunctivitis sicca (dry eye disease), the method comprising thestep of topically administering an ophthalmic composition comprising0.1% (w/v) cyclosporine dissolved in 1-(perfluorobutyl)pentane and up toabout 1.0% (w/w) ethanol to an eye of a patient; wherein the compositionis administered twice per day per eye, and as a single drop having avolume of about 8 to 10 μL; wherein the patient has at least one eyewith a total ocular surface disease index (OSDI) score of equal orgreater than 55; and wherein the patient has at least one eye with anyone or combination of criteria selected from the group consisting of:(i) a total corneal fluorescein staining score of at least 11 (NEIscale); (ii) a central corneal fluorescein staining value of about 2 to3 (NEI scale); (iii) a total lissamine green conjunctival staining scorein the range of 2 to 6; (iv) an unanesthetized Schirmer's test score inthe range of 4 to 6 mm; and (v) any one or combination of (i) to (iv);or (vi) any combination of (i) to (iv), with the specified values inboth eyes.
 36. The method of claim 35, wherein treatment is effective inreducing ocular surface damage selected from ocular surface damage ofthe central corneal region and ocular surface damage of the inferiorcorneal region.
 37. The method of claim 35, wherein the dry eye diseaseis aqueous-deficient dry eye disease.
 38. The method of claim 35,wherein the dry eye disease is evaporative dry eye disease.
 39. Themethod of claim 35, wherein the patient is non-responsive, orinsufficiently responsive to treatment with aqueous ophthalmic eye dropcompositions (e.g., aqueous cyclosporin emulsion eye drops).
 40. Themethod of claim 35, wherein the patient has a history ofkeratoconjunctivitis sicca (dry eye disease) in one or both eyes for atleast six months.
 41. The method of claim 35, wherein the patient has atleast one eye, or both eyes with any one or combination of: (i) acentral corneal fluorescein staining (NEI scale) score of 2 or higher;(ii) an inferior corneal fluorescein staining (NEI scale) score of 2 orhigher; and (iii) a total corneal fluorescein staining (NEI scale) scoreof 11 or higher.